CN116143615A - Salvianic acid A sodium I crystal form and preparation method thereof - Google Patents
Salvianic acid A sodium I crystal form and preparation method thereof Download PDFInfo
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- CN116143615A CN116143615A CN202211118497.8A CN202211118497A CN116143615A CN 116143615 A CN116143615 A CN 116143615A CN 202211118497 A CN202211118497 A CN 202211118497A CN 116143615 A CN116143615 A CN 116143615A
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- 239000013078 crystal Substances 0.000 title claims abstract description 75
- PAFLSMZLRSPALU-UHFFFAOYSA-N Salvianic acid A Natural products OC(=O)C(O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-UHFFFAOYSA-N 0.000 title claims abstract description 67
- PAFLSMZLRSPALU-MRVPVSSYSA-N (2R)-3-(3,4-dihydroxyphenyl)lactic acid Chemical compound OC(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-MRVPVSSYSA-N 0.000 title claims abstract description 66
- 239000011734 sodium Substances 0.000 title claims abstract description 62
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 61
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 27
- ZMMKVDBZTXUHFO-DDWIOCJRSA-M sodium;(2r)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate Chemical group [Na+].[O-]C(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 ZMMKVDBZTXUHFO-DDWIOCJRSA-M 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
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- 239000003814 drug Substances 0.000 claims description 14
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- 229940079593 drug Drugs 0.000 claims description 7
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- 239000003208 petroleum Chemical group 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 6
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- -1 3, 4-dihydroxyphenyl Chemical group 0.000 description 4
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 241000304195 Salvia miltiorrhiza Species 0.000 description 1
- 235000011135 Salvia miltiorrhiza Nutrition 0.000 description 1
- 229930194268 Salvianic acid Natural products 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a sodium salvianic acid A I crystal form and a preparation method thereof. The sodium salvianic acid A I crystal form:
wherein the X-ray powder diffraction pattern of the sodium salvianic acid A I crystal form is 2 θ = 9.740, 13.880, 13.900, 15.800, 16.800, 18.640, 18.900, 20.240, 22.380, 23.360, 24.280, 24.460, 26.420, 29.440, 30.340, 31.800, 32.380, and 40.540, wherein 2 θ The value error range was + -0.2. The salvianic acid A sodium I crystal form provided by the invention has the advantages of high solubility, good stability and the like, is more beneficial to formulation development, and is suitable for industrial production.
Description
Technical Field
The invention relates to a sodium salvianic acid A polymorph, in particular to a sodium salvianic acid A I polymorph, a preparation method thereof, and an active medicine and a pharmaceutical composition related to the sodium salvianic acid A polymorph.
Background
Danshensu (Danshensu) chemical name is [ D- (+) -beta- (3, 4-dihydroxyphenyl) lactic acid]Because of its unstable structure, it is usually stored as sodium salt. The molecular formula of the salvianic acid A sodium is C 9 H 9 O 5 Na, molecular weight 220.15, structural formula:
salvianic acid is one of the main active ingredients of radix Salviae Miltiorrhizae, and its pharmacological actions have been studied by scholars at home and abroad. The tanshinol has the functions of scavenging free radicals, resisting oxidation, inflammation, fibrosis, lipid peroxidation, apoptosis, autophagy and Ca 2+ Overload, platelet aggregation inhibition, thrombosis inhibition, atherosclerosis prevention, vascular endothelial cell protection, myocardial ischemia and hypoxia protection, coronary vessel expansion, endothelial progenitor cell function improvement, microcirculation improvement, mitochondrial function improvement, fat metabolism immunoregulation and other pharmacological activities, and has a protective effect on cardiovascular and cerebrovascular diseases, liver, kidney, lung and the like, and is one of main components of the traditional Chinese medicine salvia miltiorrhiza for treating cardiovascular and cerebrovascular diseases (Zhang Jinli, et al Eur J Pharmacol.2019,864:172710;Bao Xiaoyi,et al.Front Pharmacol.2018,9:1445). The wide pharmacological action of the salvianic acid A suggests that the salvianic acid A and the sodium salt thereof have wide potential treatment prospect for treating various cardiovascular and cerebrovascular diseases, and are worthy of clinical expansion research and further development.
Polymorphism is well known to be a common occurrence in solid drugs, and is one of the important factors affecting the quality and efficacy of solid drugs. Different crystal forms of the same medicine have different mechanical, thermodynamic, physical and chemical characteristics, and may be obviously different in appearance, solubility, melting point, dissolution rate, bioavailability and the like, so that the dissolution and absorption of the medicine in vivo are affected, the bioavailability and the curative effect of the medicine are further affected, adverse reactions are even generated, and the medication safety is affected.
Therefore, the crystal forms have important significance for drug development. However, up to now, the characteristics of the sodium salvianic acid A crystal form, a preparation method thereof and a pharmaceutical composition containing the crystal form are not reported in the literature.
Disclosure of Invention
The invention aims to provide a sodium salvianic acid A I crystal form and a preparation method thereof. The salvianic acid A sodium I crystal form provided by the invention has the advantages of high solubility, good stability and the like, is more beneficial to formulation development, and is suitable for industrial production.
The invention provides a sodium salvianic acid A I crystal form, whichX-ray powder diffraction pattern at 2 θ = 9.740, 13.880, 13.900, 15.800, 16.800, 18.640, 18.900, 20.240, 22.380, 23.360, 24.280, 24.460, 26.420, 29.440, 30.340, 31.800, 32.380, and 40.540, wherein 2 θ The value error range was + -0.2.
Further, the X-ray powder diffraction pattern of the sodium salvianic acid A I crystal form is shown in 2 θ Diffraction peaks are present at= 9.740, 11.420, 13.880, 13.900, 15.800, 16.800, 17.660, 18.640, 18.900, 19.120, 20.240, 22.380, 23.360, 24.280, 24.460, 26.420, 27.940, 28.500, 29.440, 30.340, 31.800, 32.380, 35.720, 36.400, 37.080, 37.660, 38.320, 38.700, 40.540, 43.400 and 44.280.
Further, the sodium danshensu form I has an XRPD pattern which is basically the same as that of figure 1 of the drawings in the specification.
The invention also provides a preparation method of the salvianic acid A sodium I crystal form, which comprises the following steps:
1) a, taking sodium salvianic acid A raw material medicine, adding water and an organic solvent, heating, stirring and dissolving;
or b, taking sodium salvianic acid A as a raw material, adding water or an organic solvent for the first time, heating, stirring and dissolving; then adding water or organic solvent for the second time, and continuing stirring for dissolving; wherein, when the first time of adding is water, adding the organic solvent for the second time; if the first time is the organic solvent, adding water for the second time;
2) And (3) continuously stirring at room temperature, filtering and drying to obtain sodium salvianic acid A crystal after a large amount of crystals are separated out.
Further, the mass volume ratio of the sodium salvianic acid A bulk drug in the step 1) to water is 1g: (1-30) mL.
Further, the organic solvent in the step 1) may be an organic solvent or a combination of ketones, ethers, alkanes, aromatic hydrocarbons, esters, nitriles, alcohols, or halogenated hydrocarbons, preferably one or more of acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, diethyl ether, tert-butyl ether, petroleum ether, tetrahydrofuran, dichloromethane, methanol, ethanol, isopropanol, and n-butanol; wherein the dosage of the organic solvent is 0.5-5 times of the dosage of water.
Further, the temperature of heating, stirring and dissolving in the step 1) is controlled to be 10-70 ℃; preferably 20 to 45 ℃.
Further, the temperature of the second time of adding water or organic solvent in the step 1) is controlled between 0 and 50 ℃ after continuous stirring and dissolution; preferably 20 to 40 ℃.
Further, the time for keeping stirring at room temperature is controlled to be 12-48 hours, preferably 24 hours.
Further, the drying treatment is specifically drying under reduced pressure in a vacuum oven at 80 ℃ for 24 hours or drying under reduced pressure with an oil pump for 12 hours.
Compared with the prior art, the invention has the beneficial effects that:
the sodium salvianic acid A crystal form I prepared by the invention has better solubility in aqueous solution and faster dissolution speed in PBS solution, is favorable for dissolution and absorption in human body, and has good dissolution characteristics, so that the novel crystal form has a larger application prospect.
The novel crystal form of the sodium salvianic acid A I prepared by the invention is stored under the conditions of high humidity (25 ℃/90% humidity), high temperature (60 ℃/air humidity) and illumination (light intensity 4500 lux+/-500 lux), has no obvious change in content, appearance, crystal form and the like, has good stability and can be better applied to pharmaceutical preparations.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern of sodium danshensu form I prepared in accordance with the present invention;
FIG. 2 is a thermal gravimetric analysis (TG) chart of sodium danshensu form I prepared by the invention;
FIG. 3 is a differential scanning calorimetric analysis (DSC) of sodium danshensu form I prepared in the present invention;
FIG. 4 is an infrared spectrum (IR) diagram of sodium danshensu I crystal form prepared by the invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum (H NMR) diagram of sodium danshensu I crystal form prepared by the invention;
FIG. 6 is a High Performance Liquid Chromatography (HPLC) diagram of sodium danshensu I crystal form prepared by the invention;
FIG. 7 is a stable X-ray powder diffraction (XRPD) pattern of 0d,10d of sodium danshensu form I prepared in accordance with the present invention under high humidity conditions;
FIG. 8 is a stable X-ray powder diffraction (XRPD) pattern of 0d,10d of sodium danshensu I crystal form prepared in the invention under high temperature conditions;
FIG. 9 is a stable X-ray powder diffraction (XRPD) pattern of 0d,10d of sodium danshensu form I prepared in the invention under illumination.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the present invention, but should not be construed as limiting the invention. It should be noted that several modifications and improvements can be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention.
The sodium danshensu used in the following examples is incorporated herein by reference in its entirety in accordance with the chinese patent application No. 202110184726.5 entitled "extraction process of high purity sodium danshensu". Is prepared.
X-ray powder diffraction (XRD) analysis: type RigakuD/Max-2500, japan: radiation source: copper targets were scanned at room temperature: scanning range is 2.0-50.0 DEG, step size: 0.02 °, scan rate: 8 DEG/min;
thermogravimetric analyzer (TG) analysis: TGA2 thermogravimetric analyzer of meltretolide, switzerland, the scanning range is 30-180 ℃ for testing the weightlessness curve, and the heating rate is set to 10 ℃ for min -1 Nitrogen protection;
differential Scanning Calorimetry (DSC) analysis: switzerland Metrele-tolidol DSC type 1, range from 30-280 ℃, heating rate: 5 ℃/min, nitrogen protection;
infrared spectroscopy (IR) analysis: samples were scanned by Spectrum 400 from Perkinelmer, USA, in the spectral scan range 4000-500cm -1 Resolution of 4.000cm -1 The number of scans was 16, measured using Attenuated Total Reflectance (ATR);
high Performance Liquid Chromatography (HPLC) to detect purity conditions: octadecylsilane chemically bonded silica was used as a filler (150 mm. Times.4.6 mm,3 μm); mobile phase is 0.5% glacial acetic acid solution-methanol (90:10); the column temperature is 28 ℃; the detection wavelength is 280nm;
nuclear magnetic hydrogen spectroscopy (H NMR) analysis: bruce 600MHz nuclear magnetic resonance NMR spectrometer, deuterium water as solvent.
The experimental methods in the following examples are conventional methods unless otherwise specified.
Example 1: preparation of sodium salvianic acid A I crystal form
Taking 10g of sodium salvianic acid A bulk drug, adding 30mL of purified water, heating to 40 ℃ for dissolution, adding 25mL of acetone, preserving heat and stirring for 1 hour, slowly cooling to room temperature, stirring and crystallizing for 12 hours, crystallizing out a large amount of crystals, and filtering; the filter cake was dried under reduced pressure in a vacuum oven at 80℃for 24 hours to give 8.3g of sodium danshensu crystals with a yield of 83%, and the HPLC profile was as shown in FIG. 5, with a purity of 99.89%.
Of products 1 The H-NMR spectrum is shown in FIG. 6, and the nuclear magnetic data are as follows:
1 H-NMR(600MHz，D 2 O)δ6.90(d，J＝8.4Hz，1H)，6.84(d，J＝1.8Hz，1H)，6.78(dd，J＝8.4,1.8Hz，1H)，4.24-4.22(m,1H)，3.02(dd，J＝14.4，4.2Hz，1H)，2.81(dd，J＝14.4，7.8Hz，1H)。
XRD detection was performed on the sample prepared in this example, and as shown in FIG. 1, the obtained crystal form was form I. Specific peak positions are shown in table 1 below.
Table 1: example 1X-ray powder diffraction data of sodium danshensu form I of the invention
It will be appreciated by those skilled in the art that in the present example, the diffraction peaks in the table do not represent an exhaustive list of diffraction peaks exhibited by the sodium danshensu form I. The 2 theta values of the X-ray powder diffraction patterns are slightly variable with machine and with variations in sample preparation and batch-to-batch variations, and the values quoted are not to be considered absolute. It will also be appreciated that the relative intensities of the peaks may vary with the effect of orientation and thus the intensities shown in the XRPD traces comprised by the present invention are exemplary and not used for absolute comparison.
The crystal samples obtained in this example were subjected to thermogravimetric analysis, differential scanning calorimetry and infrared spectroscopy, and TG spectra, DSC thermograms and infrared spectra obtained were shown in fig. 2, 3 and 4.
According to the preparation method of the embodiment, firstly, the sodium salvianic acid A is dissolved by water, then the organic solvent is added to crystallize the sodium salvianic acid A, the sodium salvianic acid A with a new crystal form is successfully prepared by the cooperation of water and the organic solvent, the purity of the obtained sodium salvianic acid A crystal is high, the purity can reach more than 99 percent through HPLC detection, and the maximum single impurity content is extremely low to be less than 0.01 percent. HPLC liquid phase purity is shown in FIG. 5.
Example 2: preparation of sodium salvianic acid A I crystal form
Taking 10g of sodium salvianic acid A bulk drug, adding 30mL of purified water, 20mL of acetone and 10mL of methanol, stirring and heating to 35 ℃ for dissolution, adding sodium salvianic acid A crystal form I seed crystal, cooling to room temperature, stirring and crystallizing for 12h, crystallizing out a large amount of crystals, and filtering; the filter cake was dried in vacuo at 60 ℃ to obtain sodium danshensu crystals, which were analyzed by X-ray powder diffraction (XRPD) and the results showed that the obtained crystal form was form i.
Example 3: high-humidity stability investigation of sodium salvianic acid A I crystal form
The solid of the sodium salvianic acid A I crystal form prepared in the example 1 is placed under the condition of high humidity (25 ℃/90% humidity) and stored for 10 days, and samples are taken at days 0 and 10, and HPLC analysis is adopted to determine the purity change of the experimental sample; x-ray powder diffraction measurements were performed using XRPD to determine the change in crystal form of the experimental samples (as shown in fig. 7). The results show that the sodium salvianic acid A I crystal form is stable under high humidity conditions (shown in Table 2).
Example 4: high temperature stability investigation of sodium salvianic acid A I crystal form
The solid of the sodium salvianic acid A I crystal form prepared in the example 1 is placed under the condition of high temperature (60 ℃/air humidity) and stored for 10 days, sampling is carried out on days 0 and 10, and HPLC analysis is adopted to determine the purity change of an experimental sample; x-ray powder diffraction measurements were performed using XRPD to determine the change in crystal form of the experimental samples (as shown in fig. 8). The detailed results of the stability of the sodium salvianic acid A I crystal form are shown in Table 2. The results show that the sodium salvianic acid A I crystal form is stable under high temperature conditions (shown in Table 2).
Example 5: light stability investigation of sodium danshensu I crystal form
The solid of sodium danshensu I crystal form prepared in the example 1 is placed under the illumination intensity of 4500lux +/-500 lux and stored for 10 days, and samples are taken at the 0 th and 10 th days, and HPLC analysis is adopted to determine the purity change of the experimental samples; x-ray powder diffraction measurements were performed using XRPD to determine the change in crystal form of the experimental samples (as shown in fig. 9). To examine the crystal form stability of the sample against light. The results show that the sodium salvianic acid A I crystal form is stable under the illumination condition (shown in table 2).
Table 2: stability investigation result of sodium salvianic acid A I crystal
The experimental results of examples 3-5 show that:
under the experimental conditions of the table, the sodium salvianic acid A I crystal form has no obvious change in content, appearance, crystal form and the like, has good stability and can be better applied to pharmaceutical preparations.
Application examples: liquid dosage forms (such as injection, solution, etc.), solid dosage forms (such as tablet, capsule, etc.), semisolid dosage forms (such as ointment, gel, etc.), gas dosage forms (such as aerosol, spray, etc.), etc. of sodium danshensu I crystal form
The injection comprises the following components: adding 20 g of sodium salvianic acid A I crystal form into 1L of water for injection for dissolution, adding 10g of sodium chloride osmotic pressure regulator, regulating the pH value to 7.0-8.0 by using dilute hydrochloric acid, filtering by a 0.22 mu m filter membrane, packaging, and sterilizing at 121 ℃ for 30 minutes to obtain the salvianic acid A.
Tablet: adding 10g of sodium salvianic acid A I crystal form into 400 g of lactose, fully mixing, adding 30% of pvp adhesive, granulating, drying, and tabletting.
And (3) capsules: adding 10g of sodium salvianic acid A I crystal form into 100 g of microcrystalline cellulose and 300 g of starch, fully mixing, adding 30% of pvc binder, granulating, drying, and filling capsules.
Ointment: 300 g of vaseline, 100 g of higher fatty alcohol and 50 g of glyceryl monostearate are heated to 80 ℃ to be melted, and filtered by a fine cloth; and 5 g of sodium laurylsulfate is dissolved in water, heated to 95deg.C, and the aqueous solution is slowly added into the oil phase under stirring to obtain emulsion matrix. Adding 10g of sodium salvianic acid A I crystal form, stirring to condense, and packaging.
Spraying agent: 9g of sodium chloride is dissolved by 800mL of water for injection, 20 g of sodium salvianic acid A I crystal form is added to dissolve, the pH is regulated to 7.0-8.0 by dilute hydrochloric acid, and the water for injection is added to be regulated to 1000mL. Filtering the prepared medicinal liquid with 0.22 μm sterilizing filter, packaging into nasal spray bottle, and capping.
Comparative example: comparison of solubility of sodium danshensu I form and commercial sodium danshensu
Sample source: the purity of the sodium salvianic acid A I crystal form prepared in the example 1 is more than 99%; the purity of the commercial sodium salvianic acid A is more than 98 percent.
The experimental method comprises the following steps: the sodium salvianic acid A crystal form I and commercial sodium salvianic acid A are fully dissolved in phosphate buffer salt solution with pH of 6.8 (the preparation method is shown in Chinese pharmacopoeia), the concentration of each solution is detected by using a high-efficiency liquid phase until the concentration is not increased any more, the final concentration is recorded, and the solubility of each crystal form is calculated according to the final concentration.
Experimental results:
table 3: solubility of sodium danshensu in different crystal forms
| Crystal form | Solubility (pH 6.8 phosphate buffer saline) |
| Sodium salvianic acid A I crystal form | 251.34mg/mL |
| Commercial sodium danshensu | 157.30mg/mL |
From the above results, the solubility of the sodium danshensu form I is greatly superior to that of commercial sodium danshensu.
While the preferred embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments, and various equivalent modifications and substitutions can be made by one skilled in the art without departing from the spirit of the present invention, and these equivalent modifications and substitutions are intended to be included in the scope of the present invention as defined in the appended claims.
Claims (10)
1. A salvianic acid A sodium I crystal form is characterized in that:
wherein the X-ray powder diffraction pattern of the sodium salvianic acid A I crystal form is shown in 2 θ = 9.740, 13.880, 13.900, 15.800, 16.800, 18.640, 18.900, 20.240, 22.380, 23.360, 24.280, 24.460, 26.420, 29.440, 30.340, 31.800, 32.380, and 40.540, with a diffraction peak at 2 θ The value error range was + -0.2.
2. The salvianic acid a sodium I crystal form according to claim 1, wherein: the X-ray powder diffraction pattern of the sodium salvianic acid A I crystal form is 2 θ Diffraction peaks are present at= 9.740, 11.420, 13.880, 13.900, 15.800, 16.800, 17.660, 18.640, 18.900, 19.120, 20.240, 22.380, 23.360, 24.280, 24.460, 26.420, 27.940, 28.500, 29.440, 30.340, 31.800, 32.380, 35.720, 36.400, 37.080, 37.660, 38.320, 38.700, 40.540, 43.400 and 44.280.
3. The salvianic acid a sodium I crystal form according to claim 1, wherein: the sodium salvianic acid A I crystal form has an XRPD pattern which is basically the same as that of figure 1 of the specification attached drawings.
4. A process for the preparation of the sodium danshensu form i according to any one of claims 1 to 3, comprising:
1) a, taking sodium salvianic acid A raw material medicine, adding water and an organic solvent, heating, stirring and dissolving;
or b, taking sodium salvianic acid A as a raw material, adding water or an organic solvent for the first time, heating, stirring and dissolving; then adding water or organic solvent for the second time, and continuing stirring for dissolving; wherein, when the first time of adding is water, adding the organic solvent for the second time; if the first time is the organic solvent, adding water for the second time;
2) And (3) continuously stirring at room temperature, filtering and drying to obtain sodium salvianic acid A crystal after a large amount of crystals are separated out.
5. The method of manufacturing according to claim 4, wherein: the mass volume ratio of the sodium salvianic acid A bulk drug in the step 1) to water is 1g: (1-30) mL.
6. The method of manufacturing according to claim 4, wherein: the organic solvent in the step 1) is selected from one or more of acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, diethyl ether, tertiary butyl ether, petroleum ether, tetrahydrofuran, dichloromethane, methanol, ethanol, isopropanol and n-butanol; wherein the dosage of the organic solvent is 0.5-5 times of the dosage of water.
7. The method of manufacturing according to claim 4, wherein: the temperature of heating, stirring and dissolving in the step 1) is controlled to be 10-70 ℃.
8. The method of manufacturing according to claim 4, wherein: and b) adding water or an organic solvent for the second time in the step 1) and continuously stirring and dissolving at the temperature of 0-50 ℃.
9. The method of manufacturing according to claim 4, wherein: the stirring time kept at room temperature is controlled to be 12-48 hours.
10. The method of manufacturing according to claim 4, wherein: the drying treatment is specifically drying under reduced pressure in a vacuum oven at 80 ℃ for 24 hours or drying under reduced pressure by an oil pump for 12 hours.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101434534A (en) * | 2007-11-12 | 2009-05-20 | 北京科士蓝医药技术有限公司 | Preparation of salvianic acid A sodium pure product |
| CN101445451A (en) * | 2008-12-30 | 2009-06-03 | 合肥紫金医药科技有限公司 | Method for preparing high-purity salvianic acid A sodium |
| CN102336652A (en) * | 2010-07-16 | 2012-02-01 | 湖南康普医药研究院 | Method for scale preparation of high-purity Danshensu sodium |
| CN102464581A (en) * | 2010-11-12 | 2012-05-23 | 天津天士力制药股份有限公司 | Method for preparing high-purity sodium danshensu |
| CN103288630A (en) * | 2012-02-27 | 2013-09-11 | 上海交通大学 | Synthesizing method of Salvianic acid A sodium |
| CN108744583A (en) * | 2018-07-12 | 2018-11-06 | 吉林龙鑫药业有限公司 | A kind of drug extraction tank and its application |
| CN114907184A (en) * | 2021-02-10 | 2022-08-16 | 上海其光药业有限公司 | Extraction process of high-purity salvianic acid A sodium |
-
2022
- 2022-09-14 CN CN202211118497.8A patent/CN116143615A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101434534A (en) * | 2007-11-12 | 2009-05-20 | 北京科士蓝医药技术有限公司 | Preparation of salvianic acid A sodium pure product |
| CN101445451A (en) * | 2008-12-30 | 2009-06-03 | 合肥紫金医药科技有限公司 | Method for preparing high-purity salvianic acid A sodium |
| CN102336652A (en) * | 2010-07-16 | 2012-02-01 | 湖南康普医药研究院 | Method for scale preparation of high-purity Danshensu sodium |
| CN102464581A (en) * | 2010-11-12 | 2012-05-23 | 天津天士力制药股份有限公司 | Method for preparing high-purity sodium danshensu |
| CN103288630A (en) * | 2012-02-27 | 2013-09-11 | 上海交通大学 | Synthesizing method of Salvianic acid A sodium |
| CN108744583A (en) * | 2018-07-12 | 2018-11-06 | 吉林龙鑫药业有限公司 | A kind of drug extraction tank and its application |
| CN114907184A (en) * | 2021-02-10 | 2022-08-16 | 上海其光药业有限公司 | Extraction process of high-purity salvianic acid A sodium |
Non-Patent Citations (3)
| Title |
|---|
| 姚静、张自强编著: "《药物冻干制剂技术的设计及应用[M]》", 30 June 2007, 中国医药科技出版社, pages: 139 - 140 * |
| 张象麟编著: "《药品技术评价文集[M]》", 30 November 2007, 中国医药科技出版社, pages: 160 - 164 * |
| 方亮主编: "《全国高等医药院校药学类第四轮规划教材药剂学第3版》", 31 March 2016, 中国医药科技出版社, pages: 49 - 50 * |
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