CN119504680A - Flavonoid compound-meglumine co-amorphous substance and preparation method thereof - Google Patents
Flavonoid compound-meglumine co-amorphous substance and preparation method thereof Download PDFInfo
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Abstract
本发明属于医药技术领域，具体涉及一种黄酮类化合物‑葡甲胺共无定形物及其制备方法。黄酮类化合物包括黄芩素、橙皮素、柚皮素、山奈酚、槲皮素、异甘草素等，该共无定形物由单一黄酮类化合物和葡甲胺组成，采用熔融骤冷法或旋转蒸发法制成。通过汉森溶解度对黄酮类化合物与葡甲胺的混溶性进行筛选。通过PXRD、DSC、FTIR对共无定形物的晶体衍射特征、热力学性质、分子间相互作用进行测定，表明其中6种黄酮类化合物与葡甲胺成功形成了共无定形体系。6种黄酮类化合物‑葡甲胺共无定形物的溶解度及溶出度显著优于黄酮类原料药，且形成的共无定形物的物理稳定性显著优于单一的无定形药物，表现出良好的成药性能。
The present invention belongs to the field of medical technology, and specifically relates to a flavonoid compound-meglumine co-amorphous substance and a preparation method thereof. Flavonoid compounds include baicalein, hesperidin, naringenin, kaempferol, quercetin, isoliquiritigenin, etc., and the co-amorphous substance is composed of a single flavonoid compound and meglumine, and is prepared by melt quenching method or rotary evaporation method. The miscibility of flavonoid compounds and meglumine is screened by Hansen solubility. The crystal diffraction characteristics, thermodynamic properties, and intermolecular interactions of the co-amorphous substance are measured by PXRD, DSC, and FTIR, indicating that 6 kinds of flavonoid compounds and meglumine successfully form a co-amorphous system. The solubility and dissolution of the 6 kinds of flavonoid compound-meglumine co-amorphous substances are significantly better than those of flavonoid raw materials, and the physical stability of the formed co-amorphous substance is significantly better than that of a single amorphous drug, showing good drug-making performance.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a flavonoid compound-meglumine co-amorphous substance and a preparation method thereof.
Background
Flavonoids are a naturally widely occurring class of polyphenols secondary metabolites, the main sources being in fruits, vegetables, cereals, herbs, flowers and seeds. Meanwhile, the flavonoid compounds have various pharmacological effects, such as antimicrobial, antiviral, anticancer, anti-inflammatory, antioxidant, neuroprotective, cardiovascular protective effects and the like. In recent years, a plurality of flavonoid compounds with different activities, such as quercetin, have the effects of resisting oxidation, dilating coronary artery and the like, baicalein has the effects of resisting bacteria, resisting viruses and the like, genistein and soyabean element have the effects of estrogen, silymarin has the effects of liver protection and the like, and the flavonoid compounds are clinically used for treating acute and chronic hepatitis, liver cirrhosis, various toxic liver damage and the like. However, flavonoids are generally poorly soluble or insoluble in water, and their lower solubility/dissolution results in a slower dissolution rate and poor oral bioavailability, and therefore, it is necessary to take a strategy to improve the solubility/dissolution deficiencies of flavonoids.
To date, various strategies (such as nanoparticles, liposomes, amorphous solid dispersions, clathrates, and self-microemulsions) aim to increase the solubility/dissolution of poorly soluble drugs. Among these strategies, breaking the drug lattice to amorphize the drug is an effective method to enhance the water solubility of poorly soluble compounds and their oral absorption. However, the high energy amorphous system is severely limited in its application due to its own thermodynamic instability during processing, storage and dissolution. Currently, amorphous solid dispersions are used to stabilize amorphous drugs by dispersing the drug in a polymer matrix with a high glass transition temperature (T g) to enhance intermolecular forces and reduce molecular mobility. However, potential incompatibilities or low compatibility between the drug and the polymeric carrier may lead to the inevitable use of more polymer to meet an effective clinical dose, resulting in a final large volume/mass of oral administration. In addition, most of the carriers of the amorphous solid dispersion are hydrophilic materials, and the carrier has strong hygroscopicity and is easy to cause the reduction of physical stability.
In recent years, drug co-amorphism is a potential alternative technology for amorphous solid dispersion, and can effectively overcome the limitation of amorphous solid dispersion, and is attracting attention. The drug co-amorphous system (CM) is a single homogeneous amorphous system formed by intermolecular non-covalent bond interactions between a drug and a small molecule ligand (biosafety small molecule excipient or another drug) using principles and methods of crystal engineering. Co-amorphous systems have shown significant improvements in the solubility/dissolution of poorly soluble drugs and their physical stability. Furthermore, drug-drug co-amorphous systems can be designed to produce combined effects, such as synergistic effects, fewer side effects, and pharmacological interactions. Therefore, the co-amorphous system of the medicine has important significance for the pre-prescription research and the preparation design of the medicine preparation, and is more and more focused and paid attention to the students at home and abroad. But both amorphous solid dispersions and drug co-amorphous systems are metastable drug amorphous systems, and there may still be a risk of recrystallization during production, dissolution and storage.
Disclosure of Invention
The invention provides a flavonoid compound-meglumine co-amorphous substance and a preparation method thereof. In order to achieve the above purpose, the present invention adopts the following technical scheme:
The flavonoid compound and meglumine co-amorphous substance is prepared by a melt quenching method or a rotary evaporation method, wherein the flavonoid compound comprises baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin, chrysin, silymarin, glycyrrhizin, epicatechin, morin, nobiletin, phloretin, galangin, genistein, taxifolin or soybean isoflavone.
The flavonoid compounds and meglumine are filtered out 13 flavonoid compounds with good miscibility with meglumine through hansen solubility calculation, wherein the flavonoid compounds comprise baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin or chrysin.
The flavonoid compounds of the present invention are preferably baicalein, hesperetin, naringenin, kaempferol, quercetin and isoliquiritigenin.
Meglumine (Meglumine, MEG), known under the chemical name N-methyl-D-glucamine, is a methylamino derivative of sorbitol, has the molecular formula C 7H7NO5, is a white or off-white crystalline powder, is readily soluble in water, slightly soluble in ethanol, and has the chemical structure: The meglumine molecular structure contains 6 hydrogen bond acceptors, 6 hydrogen bond donors (-OH) and 6 rotatable bonds, and can well participate in the formation of intermolecular hydrogen bonds. Meanwhile, the molecular structure of the flavonoid compound is complementary with that of meglumine, and the flavonoid compound generally comprises a plurality of hydrogen bond acceptors and hydrogen bond donors, and the flavonoid compound and the meglumine have high possibility of forming intermolecular hydrogen bonds. Aiming at the water-solubility defect of flavonoid compounds, the invention introduces small molecular meglumine as a ligand to prepare co-amorphous substances with flavonoid drugs, improves the solubility/dissolution of flavonoid components and improves the oral bioavailability of the flavonoid compounds.
The flavonoid compound and the meglumine are mixed according to the mol ratio of (0.25-4), preferably, the flavonoid compound is that the meglumine is=1 (0.5-2), and most preferably, the flavonoid compound is that the meglumine is=1:1.
The method for preparing the flavonoid compound-meglumine co-amorphous substance by the melt quenching method comprises the steps of uniformly mixing flavonoid compounds and meglumine in different stoichiometric ratios for 10min by adopting a vortex meter to obtain a physical mixture. And then pouring the flavonoid compound-meglumine physical mixture with different stoichiometric ratios into an aluminum foil weighing dish, spreading the mixture in an oil bath, wherein the melting temperature is 130-170 ℃, the melting time is 2-20 min, immediately taking out a sample after complete melting, placing the sample on liquid nitrogen (-196 ℃) for quenching for 2min, and carrying out vacuum drying and grinding to obtain the flavonoid compound-meglumine co-amorphous substance.
The method for preparing the flavonoid compound-meglumine co-amorphous substance by the rotary evaporation method comprises the steps of placing the flavonoid compound and the meglumine in a 100mL single-port bottle, and adding an organic solvent for ultrasonic dissolution. The solution is decompressed and rotary evaporated to remove the solvent, and then vacuum dried to obtain the flavonoid compound-meglumine co-amorphous.
Wherein the organic solvent is any one of methanol, ethanol or ethyl acetate, preferably methanol. The water bath temperature for removing the organic solvent by reduced pressure rotary evaporation is 30-60 ℃, and the rotating speed is 50-400 rpm. Preferably at 50℃and at a rotational speed of 200rpm.
The flavonoid compound-meglumine co-amorphous substance prepared by the invention is analyzed by using powder X-ray diffraction (PXRD), and a spectrogram shows a dispersed wide diffraction ring. Using Differential Scanning Calorimetry (DSC) analysis, the spectra showed a single glass transition temperature. The spectra of the co-amorphous material were shifted to some extent compared to the flavone drug substance and meglumine using Fourier Transform Infrared (FTIR) analysis.
Compared with flavonoid crystals, the flavonoid compound-meglumine co-amorphous substance has the advantages that the solubility/dissolution rate is remarkably improved and the long-time supersaturated dissolution behavior is maintained under the conditions of a hydrochloric acid buffer solution with the pH value of 1.2 and a phosphate buffer solution with the pH value of 6.8, and the flavonoid compound-meglumine co-amorphous substance has good potential for improving the in-vivo absorption and clinical application of flavonoid medicaments. The co-amorphous material exhibits higher physical stability than the amorphous material alone.
The invention has the beneficial effects that:
Aiming at the defect of poor water solubility of the flavonoid compound, the invention utilizes the crystal engineering technology to co-amorphize the flavonoid compound and meglumine, and aims to improve the solubility, dissolution and stability of the flavonoid compound so as to achieve the aim of improving the oral bioavailability of the flavonoid compound, thereby providing a new thought for the preparation development of the flavonoid compound and other insoluble drugs.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of example 1 for the preparation of a flavonoid-meglumine co-amorphous compound;
FIG. 2 is a DSC of the flavonoid-meglumine co-amorphous prepared in example 1;
FIG. 3 is an infrared spectrum of the flavonoid-meglumine co-amorphous prepared in example 1;
FIG. 4 is a graph showing comparison of dissolution curves of baicalein crystals, the physical mixture of baicalein and meglumine prepared in example 1, and the baicalein-meglumine co-amorphous material prepared in example 1 under non-sink conditions;
FIG. 5 is a graph comparing dissolution curves of hesperetin crystals, the physical mixture of hesperetin and meglumine prepared in example 1, and the hesperetin-meglumine co-amorphous prepared in example 1 under non-sink conditions;
FIG. 6 is a graph comparing dissolution curves of naringenin crystals, the physical mixture of naringenin and meglumine prepared in example 1, and naringenin-meglumine co-amorphous material prepared in example 1 under non-sink conditions;
FIG. 7 is a graph showing comparison of dissolution curves of kaempferol crystals, a physical mixture of kaempferol and meglumine prepared in example 1, and kaempferol-meglumine co-amorphous prepared in example 1 under non-sink conditions;
FIG. 8 is a graph comparing dissolution curves of quercetin crystals, a physical mixture of quercetin and meglumine prepared in example 1, and a quercetin-meglumine co-amorphous substance prepared in example 1 under non-sink conditions;
FIG. 9 is a graph comparing dissolution curves of isoliquiritigenin crystals, the physical mixture of isoliquiritigenin and meglumine prepared in example 1, and the isoliquiritigenin-meglumine co-amorphous substance prepared in example 1 under non-sink conditions;
FIG. 10 is a PXRD graph showing baicalein amorphous stability versus other values;
FIG. 11 is a PXRD pattern showing stability versus hesperetin amorphous;
FIG. 12 is a PXRD pattern showing naringenin amorphous stability versus stability;
FIG. 13 is a PXRD graph showing comparison of kaempferol amorphous stability;
FIG. 14 is a PXRD graph of quercetin amorphous form stability versus;
FIG. 15 is a PXRD graph showing comparison of stability of isoliquiritigenin amorphous form;
FIG. 16 is a PXRD pattern showing the stability of baicalein-meglumine co-amorphous prepared in example 1 versus the stability of the same;
FIG. 17 is a PXRD graph of stability versus hesperetin-meglumine co-amorphous prepared in example 1;
FIG. 18 is a PXRD pattern showing the stability of naringenin-meglumine co-amorphous prepared in example 1 versus the stability of the same;
FIG. 19 is a PXRD pattern showing the stability of kaempferol-meglumine co-amorphous prepared in example 1 versus one another;
FIG. 20 is a PXRD graph of stability versus stability of quercetin-meglumine co-amorphous prepared in example 1;
Fig. 21 is a PXRD pattern showing the stability of the isoliquiritigenin-meglumine co-amorphous form prepared in example 1.
Detailed Description
The invention is further illustrated below with reference to examples.
Example 1
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in a 150 ℃ electrothermal thermostatted oil bath for 5min, immediately after complete melting, it was rapidly quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Test 1 characterization of the flavonoid-meglumine co-amorphous of example 1, the following is specific:
1. Powder X-ray diffraction
The analysis is carried out by adopting SmartLab X-ray diffractometer (Rigaku, japan) Cu-K alpha palladium as an emission source, the tube pressure is set to be 40KV, the tube flow is set to be 40mA, the step length is 0.02 DEG, the scanning speed is 4 DEG/min, the scanning range is 2 theta, and the scanning range is 5-40 deg. Scanning the diffraction peak of the flavonoid compound-meglumine co-amorphous crystal.
As shown in fig. 1, in example 1, the diffraction peaks of the crystals of baicalein-meglumine combination, hesperetin-meglumine combination, naringenin-meglumine combination, kaempferol-meglumine combination, quercetin-meglumine combination, and isoliquiritigenin-meglumine combination in the PXRD pattern disappeared, and a diffuse broad diffraction ring was exhibited, indicating that 6 flavonoid compounds (baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin) and meglumine combination coexist in an amorphous state. Examples 2-16 of the present invention exhibited the same or similar PXRD patterns as the baicalein-meglumine combination, hesperetin-meglumine combination, naringenin-meglumine combination, kaempferol-meglumine combination, quercetin-meglumine combination and isoliquiritigenin-meglumine combination.
2. Differential scanning calorimetry
About 5mg of each of the flavonoid-meglumine co-amorphous complexes was taken and placed in an aluminum crucible, analyzed using a HITACHIDSC 7020 differential scanning thermal analyzer (Hitachi Profile, japan), and warmed from 25 ℃ to 200 ℃ at a warming rate of 10 ℃ per minute, using dry nitrogen as a carrier gas, at a flow rate of 80mL/min.
As shown in fig. 2, in example 1, the endothermic melting peaks of the flavonoid crystals of the DSC profile of baicalein-meglumine co-amorphous, kaempferol-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous were disappeared, and the temperatures were 56.2 ℃, 63.7 ℃, 58.4 ℃, 57.5 ℃, 69.9 ℃ and 59.4 ℃ respectively. Examples 2 to 16 show similar DSC patterns of baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous, showing disappearance of the crystal melting peak and single glass transition temperature, and slight differences in glass transition temperature with changes in molar ratio.
3. Infrared spectrum
Interaction between co-amorphous species was analyzed with Thermo Scientific Nicolet iS fourier transform infrared spectrometer (Thermo FISHER SCIENTIFIC, america). The flavonoid-meglumine co-amorphous was taken, ground with potassium bromide, and pressed into a sheet with a thickness of 3mm under a pressure of about 1000 pis. The scanning range is 4000-400 cm -1, and the scanning is performed 64 times with the resolution of 4cm -1.
As shown in FIG. 3, in example 1, the FTIR spectrum wavenumbers (cm -1) of baicalein-meglumine co-amorphous were ：3385.42、2926.50、1659.82、1605.87、1578.40、1447.41、1374.21、1288.12、1242.71、1179.11、1080.80、1033.66、917.12、897.81、838.81、764.27、719.58、687.25、646.00、578.41、517.40 and 433.39cm -1.
The hesperetin-meglumine co-amorphous FTIR spectrum wavenumber (cm -1) was ：3404.75、2931.00、1640.08、1514.34、1442.74、1347.22、1273.89、1181.82、1130.82、1081.74、1025.90、865.40、807.05、763.08、743.57、553.55 and 429.26cm -1.
Naringenin-meglumine co-amorphous FTIR spectrum wavenumber (cm -1) was ：3404.74、2931.00、1640.09、1514.36、1442.76、1347.22、1273.91、1181.82、1130.85、1081.89、1025.88、865.47、807.20、763.10、743.63、555.20 and 429.34cm -1.
The FTIR spectrum wavenumbers (cm -1) of kaempferol-meglumine co-amorphous were ：3404.97、2920.20、1651.86、1609.36、1560.71、1496.72、1369.14、1312.11、1257.76、1173.06、1081.43、971.90、880.76、838.88、692.78、634.31、587.52 and 516.26cm -1.
The FTIR spectrum wavenumbers (cm -1) of the quercetin-meglumine co-amorphous were ：3384.96、1601.07、1566.69、1507.84、1458.66、1361.81、1319.55、1247.48、1207.98、1169.65、1108.99、1004.46、933.94、878.63、828.53、796.74、704.42、643.86 and 464.27cm -1.
The FTIR spectrum wavenumbers (cm -1) of the isoliquiritigenin-meglumine co-amorphous material were ：3385.38、2929.89、1617.21、1493.66、1464.66、1464.97、1386.53、1362.95、1288.12、1232.38、1166.10、1084.28、839.86、626.52 and 541.53cm -1.
Test 2 saturation solubility test was performed on the flavonoid-meglumine co-amorphous of example 1, specifically as follows:
And respectively weighing excessive flavonoid compound crystals, flavonoid compound-meglumine physical mixture and flavonoid compound-meglumine co-amorphous substance, respectively dissolving in 5mL of HCl buffer solution (pH 1.2) and phosphate buffer solution (pH 6.8), placing in a 37 ℃ plus or minus 0.5 ℃ constant-temperature shaking table for shaking for 24 hours to reach solubility balance, centrifuging for 10 minutes at the rotating speed of 12000rpm, taking supernatant, passing through a 0.45 mu m microporous filter membrane and diluting by one time with methanol. And (5) taking the subsequent filtrate for HPLC analysis, and determining the concentration of the flavonoid compounds in each sample. The column used in this study was Ultimate XB-C18 (4.6 mm. Times.250 mm,5 μm), the mobile phase was acetonitrile-0.3% phosphoric acid water=60:40 (V/V), the amount of sample introduction was 10. Mu.L, the flow rate was 1.0mL/min, and 3 parts per sample were measured in parallel.
From Table 1, it can be seen that there is no significant difference in solubility of flavonoids and physical mixtures in the two media. The solubility of the flavonoid compound-meglumine co-amorphous substance in the pH 1.2HCl buffer solution is improved by 2.25-17.86 times, and the solubility of the flavonoid compound-meglumine co-amorphous substance in the pH 6.8 phosphate buffer solution is improved by 2.46-14.92 times. Therefore, by co-amorphizing the flavonoid compound with meglumine, the solubility of the flavonoid compound is significantly increased. The flavonoid-meglumine co-amorphous complexes of examples 2, 8 also exhibited significantly improved solubility.
From table 2 it can be compared that other flavonoids (chrysin, fisetin) and their solubility with meglumine melt quench products did not show a significant increase in both pH media.
TABLE 1 solubility of flavonoid crystals, flavonoid-meglumine physical mixtures and flavonoid-meglumine co-amorphous
TABLE 2 solubility of other flavonoid crystals and flavonoid-meglumine preparation (preparation method is the same as above)
Test 3. Non-leaky tank dissolution test was performed on the flavonoid-meglumine co-amorphous in example 1, specifically as follows:
Taking excessive flavonoid compound crystals, flavonoid compound-meglumine physical mixture (molar ratio 1:1) and flavonoid compound-meglumine co-amorphous substance (molar ratio 1:1), and evaluating the dissolution rate of the non-leaking tank by adopting a slurry method according to the second method of the four general rules 0931 of the 'Chinese pharmacopoeia' 2020 edition. The dissolution medium was HCl buffer at pH 1.2 and phosphate buffer at pH 6.8, the medium temperature was 37.+ -. 0.5 ℃ and stirring at 100 rpm. 2mL of each sample was taken at different times in the EP tube and simultaneously fed with an isothermal equal volume of dissolution medium. The extract was passed through a 0.45 μm microfiltration membrane and diluted one-fold with methanol, and the subsequent filtrates were subjected to HPLC analysis and peak areas were recorded separately, 3 parts per sample were measured in parallel.
As shown in fig. 4 to 9, table 3 and table 5, in example 1, the flavonoid drug substance showed similar dissolution curves with the physical mixture, but the dissolution concentration was lower, and the dissolution of baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous was significantly improved and reached the sustained maximum supersaturation concentration at 12 hours compared with the corresponding crystalline drug. The flavonoid-meglumine co-amorphous complexes of examples 2, 8 also showed significantly increased dissolution concentrations at different time points. From tables 4 and 6, it is possible to compare other flavonoid drug substances (chrysin, fisetin) and their dissolution profiles similar to those of meglumine melt quenched products in different pH media without significant improvement.
At 12h, the baicalein-meglumine co-amorphous form in example 1 was 6.17 times higher than baicalein, the hesperetin-meglumine co-amorphous form in example 1 was 5.79 times higher than hesperetin, the naringenin-meglumine co-amorphous form in example 1 was 4.33 times higher than naringenin, the kaempferol-meglumine co-amorphous form in example 1 was 4.14 times higher than kaempferol, the quercetin-meglumine co-amorphous form in example 1 was 15.15 times higher than quercetin, and the isoliquiritigenin-meglumine co-amorphous form in example 1 was 2.25 times higher than isoliquiritigenin under hydrochloric acid buffer conditions of pH 1.2.
At 12h, the baicalein-meglumine co-amorphous form in example 1 was 3.52 fold higher than baicalein, the hesperetin-meglumine co-amorphous form in example 1 was 9.17 fold higher than hesperetin, the naringenin-meglumine co-amorphous form in example 1 was 4.72 fold higher than naringenin, the kaempferol-meglumine co-amorphous form in example 1 was 25.42 fold higher than kaempferol, the quercetin-meglumine co-amorphous form in example 1 was 8.58 fold higher than quercetin, and the isoliquiritigenin-meglumine co-amorphous form in example 1 was 2.48 fold higher than isoliquiritigenin under phosphate buffer conditions of pH 6.8.
TABLE 3 dissolution concentration of flavonoid crystals and flavonoid-meglumine co-amorphous at different time points at pH 1.2 (. Mu.g/mL)
TABLE 4 dissolution concentration (μg/mL) of other flavonoid crystals and flavonoid-meglumine preparation (preparation methods as above) at different time points at pH 1.2
TABLE 5 dissolution concentration of flavonoid crystals and flavonoid-meglumine co-amorphous at various time points at pH 6.8 (. Mu.g/mL)
TABLE 6 dissolution concentrations (. Mu.g/mL) of other flavonoid crystals and flavonoid-meglumine preparation (preparation methods as above) at different time points at pH 6.8
Test 4 stability test was performed on the flavonoid-meglumine co-amorphous in example 1, specifically as follows:
Preparing baicalein amorphous substance, hesperetin amorphous substance, naringenin amorphous substance, kaempferol amorphous substance, quercetin amorphous substance and isoliquiritigenin amorphous substance by melt quenching method, firstly weighing 1g of the flavonoid compound respectively, placing into an aluminum foil plate, floating in an oil bath pot, and heating to 5 ℃ above the melting point to melt the crystal medicine. Immediately quenching in liquid nitrogen environment, drying and grinding the obtained product, and preserving for standby.
To comprehensively evaluate the stability of the co-amorphous formulation during storage, a drug stability test box of baicalein amorphous material, hesperetin amorphous material, naringenin amorphous material, kaempferol amorphous material, quercetin amorphous material, isoliquiritigenin amorphous material, baicalein-meglumine co-amorphous material, hesperetin-meglumine co-amorphous material, naringenin-meglumine co-amorphous material, kaempferol-meglumine co-amorphous material, quercetin-meglumine co-amorphous material, and isoliquiritigenin-meglumine co-amorphous material at 25 ℃ and 40 ℃ was subjected to lofting investigation, and the physical stability at different time points was evaluated by using a powder X-ray diffraction Pattern (PXRD).
As shown in fig. 10 to 15, baicalein amorphous substance, hesperetin amorphous substance, naringin amorphous substance, kaempferol amorphous substance, quercetin amorphous substance and isoliquiritigenin amorphous substance are stored at 25 ℃ and 40 ℃, and the PXRD diffractogram shows the diffraction peaks of the crystal characteristics, which shows that the baicalein amorphous substance, hesperetin amorphous substance, naringin amorphous substance and quercetin amorphous substance have been recrystallized within 14 days, and the kaempferol amorphous substance has been recrystallized within 30 days. The isoliquiritigenin amorphous form showed no characteristic diffraction peak in the PXRD diffractogram within 90 days, indicating that the isoliquiritigenin amorphous form has high physical stability.
As shown in fig. 16 to 21, in example 1, the baicalein-meglumine co-amorphous, the hesperetin-meglumine co-amorphous, the naringenin-meglumine co-amorphous, the kaempferol-meglumine co-amorphous, the quercetin-meglumine co-amorphous, and the isoliquiritigenin-meglumine co-amorphous were stored at 25 ℃ and 40 ℃ for 90 days, and no characteristic diffraction peak was shown in the PXRD diffractogram, which showed that the baicalein-meglumine co-amorphous has high physical stability.
Example 2
Baicalein (204.52 mg) -meglumine (295.45 mg), hesperetin (218.19 mg) -meglumine (281.81 mg), naringenin (205.42 mg) -meglumine (294.58 mg), kaempferol (211.50 mg) -meglumine (288.49 mg), quercetin (218.17 mg) -meglumine (281.83 mg), isoliquiritigenin (198.13 mg) -meglumine (301.87 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in a 150 ℃ electrothermal thermostatted oil bath for 5min, immediately after complete melting, it was rapidly quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Example 3
About baicalein (367.33 mg) -meglumine (132.67 mg), hesperetin (377.96 mg) -meglumine (122.04 mg), naringenin (368.05 mg) -meglumine (131.95 mg), kaempferol (373.86 mg) -meglumine (127.14 mg), quercetin (377.94 mg) -meglumine (122.06 mg), isoliquiritigenin (362.08 mg) -meglumine (137.92 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in a 150 ℃ electrothermal thermostatted oil bath for 5min, immediately after complete melting, it was rapidly quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Example 4
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in a 130 ℃ electrothermal thermostatted oil bath for 5min, immediately after complete melting, it was rapidly quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Example 5
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in an electrothermal thermostatted oil bath at 170 ℃ for 5min, after complete melting, immediately quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Example 6
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in a 150 ℃ electrothermal constant temperature oil bath for 2min, after complete melting, immediately quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Example 7
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) were weighed separately, placed in an EP tube, and vortex mixed for 10min. The flavonoid-meglumine physical mixture was transferred to an aluminum foil weigh dish and heated in a 150 ℃ electrothermal thermostatted oil bath for 20min, immediately after complete melting, it was rapidly quenched with liquid nitrogen. Subsequently, it was ground to dryness and stored dry at 4 ℃ after sealing.
Example 8
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL methanol is added, and the solution is dissolved by ultrasound to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at a speed set at 200rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 9
Baicalein (204.52 mg) -meglumine (295.45 mg), hesperetin (218.19 mg) -meglumine (281.81 mg), naringenin (205.42 mg) -meglumine (294.58 mg), kaempferol (211.50 mg) -meglumine (288.49 mg), quercetin (218.17 mg) -meglumine (281.83 mg), isoliquiritigenin (198.13 mg) -meglumine (301.87 mg) were weighed separately, placed in a 100mL single-mouth bottle, 50mL methanol was added, and the solution was obtained by ultrasonic dissolution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at a speed set at 200rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 10
About baicalein (367.33 mg) -meglumine (132.67 mg), hesperetin (377.96 mg) -meglumine (122.04 mg), naringenin (368.05 mg) -meglumine (131.95 mg), kaempferol (373.86 mg) -meglumine (127.14 mg), quercetin (377.94 mg) -meglumine (122.06 mg), isoliquiritigenin (362.08 mg) -meglumine (137.92 mg) were weighed separately, placed in 100mL single-mouth bottles, 50mL methanol was added, and the solution was obtained by ultrasonic dissolution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at a speed set at 200rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 11
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL methanol is added, and the solution is dissolved by ultrasound to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 40 ℃ water bath at a speed set to 200rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 12
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL methanol is added, and the solution is dissolved by ultrasound to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 60℃water bath at a speed set at 200rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 13
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL ethanol is added, and the mixture is dissolved by ultrasound to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at a speed set at 200rpm. After the ethanol is completely volatilized, a corresponding solid sample is obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 14
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL ethyl acetate is added, and the solution is obtained by ultrasonic dissolution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at a speed set at 200rpm. After complete volatilization of the ethyl acetate, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 15
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL methanol is added, and the solution is dissolved by ultrasound to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at a speed set at 50rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Example 16
Baicalein (290.30 mg) -meglumine (209.70 mg), hesperetin (303.80 mg) -meglumine (196.20 mg), naringenin (291.20 mg) -meglumine (208.80 mg), kaempferol (297.26 mg) -meglumine (202.74 mg), quercetin (303.78 mg) -meglumine (196.22 mg), isoliquiritigenin (283.80 mg) -meglumine (216.20 mg) are weighed separately, placed in a 100mL single-mouth bottle, 50mL methanol is added, and the solution is dissolved by ultrasound to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50 ℃ water bath at 400rpm. After complete volatilization of the methanol, a corresponding solid sample was obtained. The sample is taken out from the rotary steaming instrument, placed in a vacuum drying oven and dried for 24 hours at room temperature, residual organic solvent is removed, and the powder after sieving is sieved by a 80-mesh sieve, sealed and then dried and stored at 4 ℃.
Test 5 hansen solubility calculations were performed on flavonoid-meglumine co-amorphous, specifically as follows:
By carrying out hansen solubility parameter (delta) calculation through Molecular Modeling Pro software, screening out flavonoid medicines with good miscibility with meglumine according to solubility parameter difference (delta), and from table 7, it can be seen that 13 flavonoid compounds (baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin and chrysin) have good miscibility with meglumine. Whereas rotenone, chalcone, galangin, taxifolin, etc. have poor miscibility with meglumine.
TABLE 7 Hansen solubility parameters (delta) for flavonoid crystals and meglumine crystals
Examples 2 to 16 show the same or similar FTIR spectra as the baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous, and isoliquiritigenin-meglumine co-amorphous.
Claims (8)
1. A flavonoid compound-meglumine co-amorphous substance is characterized in that the co-amorphous substance is prepared from flavonoid compounds and meglumine by a melt quenching method or a rotary evaporation method, wherein the flavonoid compounds comprise baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin, chrysin, silymarin, glycyrrhizin, epicatechin, morin, nobiletin, phloretin, galangin, genistein, taxifolin or soybean isoflavone.
2. The flavonoid-meglumine co-amorphous compound according to claim 1, wherein the flavonoid is baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin or chrysin.
3. The flavonoid-meglumine co-amorphous according to claim 1, wherein said flavonoid is baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin.
4. The flavonoid-meglumine co-amorphous compound according to claim 1, wherein the molar ratio of the flavonoid to the meglumine is 1:0.25-4.
5. The flavonoid-meglumine co-amorphous compound according to claim 1, wherein the molar ratio of the flavonoid to the meglumine is 1:0.5-2.
6. The flavonoid-meglumine co-amorphous compound according to claim 1, wherein the melting temperature of the melting quenching method is 130-170 ℃ and the melting time is 2-20 min.
7. The flavonoid-meglumine co-amorphous compound according to claim 1, wherein the water bath temperature of the rotary evaporation method is 30-60 ℃ and the rotation speed is 50-400 rpm.
8. The flavonoid-meglumine co-amorphous compound according to claim 1, wherein the organic solvent used in the rotary evaporation method is any one of methanol, ethanol and ethyl acetate.
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