CN115925662A - Novel crystal form of salvianolic acid C and preparation method thereof - Google Patents
Novel crystal form of salvianolic acid C and preparation method thereof Download PDFInfo
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- GCJWPRRNLSHTRY-UHFFFAOYSA-N Salvianolic acid C Natural products C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)=CC=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 GCJWPRRNLSHTRY-UHFFFAOYSA-N 0.000 title claims abstract description 80
- GCJWPRRNLSHTRY-VURDRKPISA-N Salvianolic acid C Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2C=C(OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 GCJWPRRNLSHTRY-VURDRKPISA-N 0.000 title claims abstract description 77
- 239000013078 crystal Substances 0.000 title claims abstract description 36
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- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 description 1
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- NFOCYHUCMXEHDG-UHFFFAOYSA-N Monomethyl lithospermate Natural products COC(=O)C1C(C=2C=C(O)C(O)=CC=2)OC(C(=CC=2)O)=C1C=2C=CC(=O)OC(C(O)=O)CC1=CC=C(O)C(O)=C1 NFOCYHUCMXEHDG-UHFFFAOYSA-N 0.000 description 1
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Images
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a novel crystal form of salvianolic acid C and a preparation method thereof. Compared with amorphous powder, the novel salvianolic acid C crystal form has higher purity and stability. The preparation method of the new salvianolic acid C crystal form is simple and easy to implement, has lower cost, is easy for industrial amplification, and can be used as a raw material of various new pharmaceutical preparations of salvianolic acid C.
Description
Technical Field
The invention relates to the field of medical chemistry, in particular to a novel crystal form of salvianolic acid C and a preparation method thereof.
Background
Salvia miltiorrhiza is one of the common traditional Chinese medicines for treating cardiovascular diseases, and has a long history of clinical application. The water-soluble effective component is a plurality of phenolic acid compounds composed of caffeic acid polymers, including rosmarinic acid, lithospermic acid, salvianolic acid A, B, C and the like, wherein the tripolymer and tetramer of caffeic acid are considered as the most active compounds.
The application of traditional Chinese medicines is mainly water decoction, so that the water-soluble components of salvia miltiorrhiza are more and more concerned. Salvianolic acid C is a water-soluble caffeic acid trimer phenolic acid compound naturally existing in Saviae Miltiorrhizae radix. Research shows that the salvianolic acid C has pharmacological effects in many aspects, including stronger xanthine oxidase inhibition activity so as to be used for hyperuricemia and complications thereof, inhibition of cell oxidative stress and cell apoptosis mediated by the cell oxidative stress, inhibition of inflammatory reaction to resist nerve cell damage, induction of tumor cell apoptosis, anti-new coronavirus effect and the like, and has better application prospect.
However, the existing salvianolic acid C products are all in an amorphous state, and the purity of industrial products is low (generally lower than 95%). Salvianolic acid C in an amorphous state has poor stability, is easily degraded during storage at room temperature, is also easily discolored (from original light yellow to brown), and is easily hygroscopic. In addition, the product with the purity of 95 percent is difficult to meet the raw material requirement of new medicine development, and particularly when the product is used as a raw material of a chemical injection, the residual 5 percent of impurities significantly increase the quality research work of the new medicine development and bring more risks to clinical use. Therefore, the method has important value for developing a salvianolic acid C product with higher purity and better stability and a preparation process capable of meeting the industrial production of new drugs.
Disclosure of Invention
The invention aims to provide a novel crystal form of salvianolic acid C and a preparation method thereof.
In a first aspect of the present invention, there is provided a crystalline form of salvianolic acid C having a characteristic peak at 2 θ ± 0.2 ° in an X-ray powder diffraction pattern, where 2 θ comprises: 4.7 °, 8.2 °, and 9.5 °.
In another preferred example, the 2 θ further comprises one or more values selected from the group consisting of: 12.7 °, 13.3 °, and 14.5 °.
In another preferred example, the 2 θ includes: 4.695 °, 8.243 °, and 9.534 °.
In another preferred example, the 2 θ further comprises one or more values selected from the group consisting of: 12.727 °, 13.322 °, and 14.469 °.
In another preferred embodiment, the 2 θ includes 3 or more than 3 values selected from the group consisting of: 4.695 °, 8.243 °, 9.534 °, 12.727 °, 13.322 °, and 14.469 °.
In another preferred example, the 2 θ is 4.695 °, 8.243 °, 9.534 °, 12.727 °, 13.322 ° and 14.469 °.
In another preferred embodiment, the crystalline form of salvianolic acid C has an X-ray powder diffraction pattern substantially as characterized in fig. 3.
In another preferred embodiment, the crystalline form of salvianolic acid C has a DSC (differential scanning calorimetry) profile substantially as characterized in figure 4.
In another preferred embodiment, the TGA (thermogravimetric analysis) profile of the crystalline form of salvianolic acid C is substantially as characterized in figure 5.
In a second aspect of the present invention, a method for preparing the salvianolic acid C crystal form according to the first aspect of the present invention is provided, which comprises the following steps:
(1) Providing a solution of a salvianolic acid C material in a solvent comprising water, alcohols, or combinations thereof; and
(2) And carrying out crystallization treatment on the solution, and collecting precipitated solids to obtain the crystal form.
In another preferred embodiment, the solvent comprises water and/or ethanol, and preferably, the solvent is an ethanol aqueous solution.
In another preferred embodiment, the solvent is a 0-50% ethanol aqueous solution at final concentration (v/v), preferably a 20-40% ethanol aqueous solution, more preferably a 30% ethanol aqueous solution.
In another preferred embodiment, the purity of the salvianolic acid C raw material is greater than or equal to 90%, and preferably, the salvianolic acid C raw material comprises salvianolic acid C amorphous substance and/or salvianolic acid C crystal (such as the crystal form of the first aspect of the invention).
In another preferred embodiment, the step (1) comprises providing a first solution of salvianolic acid C in ethanol, and mixing the first solution with water to obtain the solution in the step (1).
In another preferred embodiment, the concentration of the salvianolic acid C in the first solution is 5-15% (w/v); preferably about 10% (w/v).
In another preferred embodiment, said step (1) maintains the temperature of said solution at 40-60 ℃, preferably about 50 ℃.
In another preferred example, in the step (2), firstly, salvianolic acid C seed crystals are added into the solution, and then, the solution is subjected to crystallization treatment.
In another preferred example, the crystallization treatment in step (2) comprises cooling crystallization, preferably, the solution is cooled to 0 ℃ to 30 ℃ for crystallization, preferably slowly cooled, more preferably slowly cooled to 25 ℃ first and then slowly cooled to 0 ℃.
In another preferred embodiment, the cooling rate is controlled to be 0.05-0.15 deg.C/min (preferably about 0.1 deg.C/min).
In another preferred example, the crystallization treatment in step (2) further comprises stirring.
In another preferred embodiment, the step (2) further comprises a filtering and drying step.
In another preferred embodiment, the preparation method of the salvianolic acid C seed crystal comprises the following steps:
(a) Dissolving salvianolic acid C amorphous powder in absolute ethanol at a first temperature to obtain salvianolic acid C ethanol solution;
(b) Maintaining the first temperature, adding water into the salvianolic acid C ethanol solution while stirring until turbidity appears, and obtaining a crystallization system;
(c) Maintaining stirring, cooling the crystallization system to a second temperature, further cooling to a third temperature, and maintaining the third temperature for crystallization.
In another preferred embodiment, the first temperature is 40-60 ℃, preferably about 50 ℃.
In another preferred embodiment, the second temperature is 20-30 ℃, preferably about 25 ℃.
In another preferred embodiment, the third temperature is between 0 ℃ and 5 ℃, preferably about 0 ℃.
In another preferred embodiment, the concentration of salvianolic acid C in the salvianolic acid C ethanol solution is 5-15% (w/v); preferably about 10% (w/v).
In another preferred embodiment, the crystallization system is cooled from the first temperature to the second temperature by controlling the cooling rate to be 0.05-0.15 ℃/min (preferably about 0.1 ℃/min).
In another preferred embodiment, the crystallization system is cooled from the second temperature to the third temperature by controlling the cooling rate to be 0.05-0.15 ℃/min (preferably about 0.1 ℃/min).
In another preferred example, the time for maintaining the third temperature for crystallization is 8-24h; preferably about 12 hours.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising the crystalline form of the first aspect of the invention and a pharmaceutically acceptable carrier.
In a fourth aspect of the invention, there is provided a use of the crystalline form according to the first aspect of the invention, the use comprising:
1) Preparing a salvianolic acid C compound or a salt thereof;
2) Preparing medicine for treating cardiovascular disease, hyperuricemia and complication, inflammation reaction, cancer and/or new coronavirus infection.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a photomicrograph (magnification 10X 10) of a salvianolic acid C crystal prepared by the invention
FIG. 2 HPLC chromatogram before and after crystallization of salvianolic acid C
FIG. 3 is an X-ray powder diffraction pattern of salvianolic acid C crystal prepared by the present invention and related parameters
FIG. 4 DSC (differential scanning calorimetry) profile of crystalline salvianolic acid C prepared according to the invention
FIG. 5 TGA (thermogravimetric analysis) profile of crystalline salvianolic acid C prepared by the present invention
Detailed Description
The inventor of the invention unexpectedly discovers a new crystal form of salvianolic acid C, a preparation method and an application thereof for the first time through extensive and intensive research. The novel crystal form has more excellent stability (including high-temperature stability, high-humidity stability and illumination stability), higher purity, lower hygroscopicity and high bioavailability, and can be used as a raw material of various novel salvianolic acid C preparations. Meanwhile, the preparation method has the advantages of high yield, high purity, simplicity, practicability, lower cost and easy industrial amplification. The present invention has been completed based on this finding.
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.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of or" consisting of 823030A ".
As used herein, the term "n or more than n 2 θ values selected from the group" is meant to include n as well as any positive integer greater than n (e.g., n +1, \8230; where the upper bound Nup is the number of all 2 θ peaks in the group. For example, "3 or more" includes not only 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, \ 8230and the upper limit Nup each positive integer but also ranges such as "4 or more", "5 or more", "6 or more".
As used herein, the "slow cooling" means, for example, slowly cooling from 50 ℃ to 25 ℃ (cooling time is 3-5h, such as 4 h), and further slowly cooling to 0 ℃ (cooling time is 3-5h, such as 4 h).
As used herein, the salvianolic acid C compound has the following structural formula:
the solid is present either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (this property is known as "polymorphism"), forming crystals with different crystalline forms, each of which is known as a "polymorph". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing pattern, flowability, and/or solid state stability.
Polymorphic forms of a compound may exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, bioactivity, flowability, and the like, which are important factors affecting drug potency.
As used herein, "crystal," "crystal of the present invention," or "polymorph" are used interchangeably to refer to the crystalline form of the first aspect of the present invention.
Crystallization of
Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallography, third edition, J W Mullins, butterworth-Heineman Ltd.,1993, ISBNN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
The present invention is further illustrated by the following examples, which are provided for the purpose of illustration only and are not intended to limit the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims. The test materials and reagents used in the following examples are commercially available without specific reference. The normal temperature or room temperature is 4-25 deg.C, preferably 15-25 deg.C.
EXAMPLE 1 preparation of crystalline Salvianolic acid C from amorphous Salvianolic acid C
The preparation method of the amorphous salvianolic acid C adopted in the embodiment is as follows:
30g of salvianolic acid A (which can be obtained from commercial sources or prepared by a method in a patent ZL 201310487751.6) is prepared into 300g of an aqueous solution with the mass concentration of 10%, 300g of glacial acetic acid is added, 10g of ferrous chloride solution (with the concentration of 1 mg/g) is added, and the reaction system is cooled to 4 ℃ and stirred. Slowly dripping 20g of 20% (w/w) hydrogen peroxide solution into the reaction system, continuously stirring at low temperature for reaction, stopping the reaction after 120min to obtain an oxidation product, namely a crude product of salvianolic acid C (wherein the salvianolic acid C contains about 15 g), and dissolving the oxidation product in 20% ethanol (v/v).
Taking 1L of resin HZ816 (Shanghai Huazhen science and technology Co., ltd, china eastern science and technology university), and after the resin is processed, column packing (column diameter 6 cm) is carried out for standby by referring to the use instruction.
The salvianolic acid C solution is adsorbed by a resin column, then the resin column is eluted by sequentially adopting 20% (v/v) ethanol 6L and 40% (v/v) ethanol 6L, the resin column is continuously eluted by adopting 60% (v/v) ethanol, 500 mL/bottle is collected step by step, the effluent is detected by HPLC, and the salvianolic acid C sample with the HPLC purity of more than 80% is combined.
Mixing salvianolic acid C samples, concentrating to remove ethanol, adjusting pH to 7.00 to obtain clear solution, slowly adding hydrochloric acid to adjust pH to 2.00 during stirring, so that the solution is gradually turbid, precipitates appear, gradually cooling, filtering, precipitating, drying at normal temperature by using a dryer with phosphorus pentoxide as a drying agent to obtain salvianolic acid C solid powder 10.6g with purity of 90.2%, wherein the salvianolic acid C solid powder is irregular under a microscope and shows an amorphous state by X-ray powder diffraction, and comparing with a salvianolic acid C standard product (purchased from Shanghai Tongtian biotechnology, ltd.) to confirm that the salvianolic acid C is the salvianolic acid C.
Dissolving salvianolic acid C amorphous powder 1.0g (purity 90.2%) in 10mL of anhydrous ethanol, keeping the temperature of a water bath at 50 ℃, adding water under stirring until turbidity appears (about 4-5g of water is added), stopping heating the water bath, keeping stirring, slowly cooling the water bath to 25 ℃ (cooling time is 4 h), further slowly cooling to 0 ℃ (cooling time is 4 h), keeping the temperature at 0 ℃, continuing stirring for 12h, showing that a large amount of crystals are separated out, and quickly filtering to obtain crystals 703mg.
The crystalline state was observed under a microscope (FIG. 1), HPLC analysis (FIG. 2), and X-ray powder diffraction pattern analysis (FIG. 3), differential scanning calorimetry analysis (DSC) (FIG. 4), and thermogravimetric analysis (TGA) (FIG. 5)
The salvianolic acid C crystals prepared in this example were used as seed crystals in the subsequent examples.
The HPLC detection conditions were as follows:
and (3) chromatographic column: zorbax SB-Aq 4.6 x 250mm 5um
Column temperature: 25 deg.C
Flow rate: 1.2mL/min
Detection wavelength: 286nm
Sample introduction amount: 10ul of
Mobile phase: a:0.05% trifluoroacetic acid solution B: acetonitrile: methanol (17-8)
EXAMPLE 2 Salvianolic acid C crystallization solvent System Studies
Using a method similar to that of example 1, several amorphous salvianolic acid C powders (purity about 90%) were selected and divided into 1g portions, and anhydrous ethanol (salvianolic acid C concentration 10% (w/v)) or pure water (salvianolic acid C concentration 2% (w/v)) was added to dissolve at 50 ℃.
In the anhydrous ethanol dissolving group, water is further added respectively to make the ethanol concentration (v/v) of the system reach 50%, 40%, 30%, 20% and 10% respectively.
About 10mg of the crystalline powder prepared in example 1 was added to each treatment, the temperature was slowly lowered to 25 ℃ in a water bath (cooling time 4 hours), then further slowly lowered to 0 ℃ at 0 ℃ (cooling time 4 hours), the temperature was maintained at 0 ℃, and stirring was continued for 12 hours, so that crystals were separated out, and crystals were obtained by rapid filtration. The analysis result of X-ray powder diffraction pattern shows that the crystal forms obtained by each group are consistent with the crystal seeds.
The purity of the prepared crystals was checked by HPLC, and the yield was calculated, with the statistical results as follows:
the results show that the purity of the salvianolic acid C can be obviously improved by a crystallization means within 0-50% of the ethanol concentration of a crystallization system, and the yield is gradually reduced along with the improvement of the ethanol concentration, and the purity of the product is continuously improved. In terms of yield and purity, the concentration of ethanol in the crystallization system is selected to be 0-50% (v/v), preferably 30-50% (v/v).
EXAMPLE 3 comparison of the stability of crystalline and amorphous powders of salvianolic acid C
The stability is one of important factors influencing the drug property, the stability of the drug must be ensured within the shelf life, and degradation products with obvious toxicity are not generated, so that the drug safety within the shelf life is ensured. Generally, according to the relevant guidelines of chemical research, impurities with a content of more than 0.1% are required to be qualitatively, quantitatively or even safely studied. The methods of low temperature, drying, deoxidation and the like can obviously improve the stability of the medicine, but can also obviously increase the cost of the medicine and the operability of clinical application. The stability of the medicine can be obviously improved by adding the protective agent, but the safety of the protective agent is also more problematic. Therefore, the compound can still maintain better stability (for example, the compound can not be degraded to generate more than 0.1 percent of impurities) after being stored for a long time (for example, 36 months) at room temperature (25 ℃), and has important significance for the research, the production and the use of the medicine.
The influence factor test is an important method for drug stability investigation, can preliminarily understand the drug stability in a short time, has important significance for subsequent new drug development, and is carried out on all drugs.
The influence factor test comprises a high temperature test, a high humidity test and a strong light irradiation test. In this example, the test method described in the "Chinese pharmacopoeia" 2020 edition fourth part, page 457 is briefly described as follows:
the test article is put into a proper open container (such as a weighing bottle or a culture dish) and is spread into a thin layer with the thickness less than or equal to 5mm, and the following tests are carried out:
high-temperature test: the sample is placed in a clean container with an opening, and is sampled for HPLC detection after being placed at the temperature of 60 ℃ for 10 days, and is compared with the sample at the time of 0 day.
High humidity test: the opening of the test sample is placed in a constant humidity closed container, the test sample is placed under the condition of 90 +/-5% relative humidity for 10 days at the temperature of 25 ℃, then sampling HPLC detection is carried out, and the weight of the sample before and after the placement is recorded, so as to examine the moisture absorption condition of the sample. (selection of KNO 3 The saturated solution is placed in a closed container together to create a high-humidity environment: relative humidity 92.5% at 25 deg.c) and compared to the sample at day 0.
Strong light irradiation test: the opening of the sample is placed in a lighting box provided with a fluorescent lamp, the sample is sampled and subjected to HPLC detection after being irradiated for 10 days under the condition of the illumination of 4500lx +/-500 lx, the appearance change of the sample is observed, and the sample is compared with the sample at 0 day.
The salvianolic acid C crystal used in this example was prepared by the method of example 2.
The salvianolic acid C amorphous powder was prepared according to the method of example 1, wherein during the resin column chromatography, the eluent with HPLC purity over 95% was collected to obtain a higher purity salvianolic acid C amorphous powder (purity 96.5%) sample.
The respective products were analyzed by HPLC, and the resulting influential test results are summarized below (appearance and/or purity):
as can be seen from the above table, the amorphous salvianolic acid C is unstable under high temperature and strong light irradiation conditions, has slightly better stability than the former two under high humidity conditions, is easy to absorb moisture, and finally is in the shape of viscous oil drops. The stability of the salvianolic acid C crystal under corresponding influence factor conditions is far better than that of amorphous powder, only a small amount of degradation is caused (because the influence factor conditions are very harsh), and the product is not easy to absorb moisture.
In conclusion, the new crystal form of the salvianolic acid C is remarkably better than amorphous powder in stability, and the pharmaceutical property is higher.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concept. Therefore, the technical solutions that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concepts of the present invention and the prior art are all within the scope of protection defined by the claims.
Claims (10)
1. A crystalline form C of salvianolic acid having an X-ray powder diffraction pattern with a characteristic peak at 2 Θ ± 0.2 °, the 2 Θ comprising: 4.7 °, 8.2 °, and 9.5 °.
2. The crystalline form of salvianolic acid C of claim 1, wherein 2 Θ is 4.695 °, 8.243 °, 9.534 °, 12.727 °, 13.322 °, and 14.469 °.
3. The crystalline form of salvianolic acid C of claim 1, wherein the crystalline form of salvianolic acid C has an X-ray powder diffraction pattern substantially as characterized in figure 3.
4. A method of preparing the crystalline form of salvianolic acid C of any of claims 1-3, comprising the steps of:
(1) Providing a solution of a salvianolic acid C material in a solvent comprising water, alcohols, or combinations thereof; and
(2) And carrying out crystallization treatment on the solution, and collecting precipitated solids to obtain the crystal form.
5. The method of claim 4, wherein the solvent comprises water and/or ethanol, preferably the solvent is an aqueous ethanol solution.
6. The process according to claim 4 or 5, wherein the solvent is a 0-50% aqueous ethanol solution, preferably a 20-40% aqueous ethanol solution, more preferably a 30% aqueous ethanol solution, at final concentration (v/v).
7. The method of claim 4, wherein the salvianolic acid C raw material has a purity of at least 90%, preferably the salvianolic acid C raw material comprises salvianolic acid C amorphous matter and/or salvianolic acid C crystal.
8. The method of claim 4, wherein step (1) comprises providing a first solution of salvianolic acid C in ethanol, and mixing the first solution with water to obtain the solution of step (1).
9. A pharmaceutical composition comprising the crystalline form of any one of claims 1-3 and a pharmaceutically acceptable carrier.
10. Use of the crystalline form according to any one of claims 1 to 3, which comprises:
1) Preparing a salvianolic acid C compound or a salt thereof;
2) Preparing medicine for treating cardiovascular disease, hyperuricemia and its complication, inflammation reaction, cancer and/or new coronavirus infection.
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CN112516132A (en) * | 2020-05-18 | 2021-03-19 | 南方医科大学 | Application of salvianolic acid C or pharmaceutically acceptable salt thereof in preparing antiviral drug |
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