CN110613853B - Co-amorphous compound for improving water solubility of ursolic acid and preparation process thereof - Google Patents
Co-amorphous compound for improving water solubility of ursolic acid and preparation process thereof Download PDFInfo
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- CN110613853B CN110613853B CN201911038368.6A CN201911038368A CN110613853B CN 110613853 B CN110613853 B CN 110613853B CN 201911038368 A CN201911038368 A CN 201911038368A CN 110613853 B CN110613853 B CN 110613853B
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- 229940096998 ursolic acid Drugs 0.000 title claims abstract description 70
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 title claims abstract description 70
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 title claims abstract description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims abstract description 77
- 229960001285 quercetin Drugs 0.000 claims abstract description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims abstract description 39
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims abstract description 39
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims abstract description 39
- 235000005875 quercetin Nutrition 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 36
- 238000010438 heat treatment Methods 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 23
- 235000019441 ethanol Nutrition 0.000 abstract description 17
- 229920000642 polymer Polymers 0.000 abstract description 17
- 239000007962 solid dispersion Substances 0.000 abstract description 7
- 238000002390 rotary evaporation Methods 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 239000011521 glass Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 239000002552 dosage form Substances 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 2
- 230000007721 medicinal effect Effects 0.000 abstract description 2
- 102000003743 Relaxin Human genes 0.000 abstract 1
- 108090000103 Relaxin Proteins 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 13
- 238000000227 grinding Methods 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 9
- 239000000178 monomer Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
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- 238000011049 filling Methods 0.000 description 2
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- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
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- 230000009286 beneficial effect Effects 0.000 description 1
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- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
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- 239000012467 final product Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
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- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- -1 pentacyclic triterpenoid compounds Chemical class 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention discloses a co-amorphous compound for improving the water solubility of ursolic acid and a preparation process thereof. Adding ursolic acid and relaxin into absolute ethyl alcohol respectively, heating in a water bath for dissolving to obtain an ursolic acid alcohol solution and a quercetin alcohol solution, then pouring the quercetin alcohol solution into the ursolic acid alcohol solution according to the mass ratio of the ursolic acid to the quercetin of 1.02-0.2, uniformly mixing, and performing rotary evaporation to obtain the ursolic acid-quercetin co-amorphous compound. The invention uses two active medicinal components, namely ursolic acid and quercetin, as a method for preparing a medicament-medicament amorphous system, and uses quercetin as a ligand, and utilizes the glass state forming capability of the quercetin to form a stable amorphous compound with the ursolic acid, so as to increase the water solubility of the ursolic acid and improve the oral absorption and the medicinal effect of the ursolic acid. The compound of the invention overcomes the defects that the volume of the final dosage form is increased due to the addition of a large amount of polymer in a polymer solid dispersion, and the stability of the polymer is reduced due to the hygroscopicity of the polymer.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a co-amorphous compound for improving the water solubility of ursolic acid and a preparation process thereof.
Background
In order to solve the problems of difficult water solubility and low dissolution rate of the medicine, a plurality of preparation technologies are applied, such as micronization, cyclodextrin inclusion, solid dispersion, cosolvent and solubilizer, new preparation forms such as microemulsion and liposome and the like are adopted, salt forming treatment is carried out on the medicine, and the like.
Generally, the amorphous state of a drug has higher solubility than the crystalline state, and can promote absorption and improve oral bioavailability, but the stability of a single amorphous drug is poor. The solid dispersion preparation can change the medicine from a crystal state to an amorphous state, maintain a relatively stable amorphous state, increase the solubility and the dissolution rate, and improve the bioavailability. However, the poor solubility of drugs in polymers in polymer solid dispersions (PASD) often results in the addition of large amounts of polymer, increasing the volume of the final dosage form, and in addition most polymers are hygroscopic, decreasing their stability.
Over the past few years, co-amorphous drug systems (CAM) have been proposed and rapidly developed as a potential drug delivery system (Rahul B Chavana et al, 2016). A medicine and a small molecular excipient (auxiliary material) or a binary co-amorphous system can be formed between the two medicines, and the CAM can be used as a promising method for replacing PASD, particularly exists in the form of medicine-medicine CAM, can be used as a combined treatment medicine, can improve the water solubility and the dissolution rate of two indissolvable medicines, can also enhance the curative effect and reduce the toxic and side effect of the medicine, and part of the system even has the potential of synergistic medicine release.
The preparation method and process variables of the co-amorphous compound affect the structural characteristics of the final product, and common preparation methods include a melt quenching method, a solvent volatilization method, a solvent-spray (freeze) drying method, a co-grinding method and the like. When preparing the co-amorphous drug, the preparation method, the component proportion and the temperature are selected according to the properties of the drug.
Ursolic acid is a pentacyclic triterpenoid, belongs to low-solubility and low-permeability medicines, and belongs to a fourth class of medicines in the biopharmaceutics classification system BCS (biopharmaceutics classification system). The ursolic acid with higher purity is white powder, is white needle-shaped crystal in ethanol, and has the problems of poor solubility, oral absorption and discharge, low bioavailability, high in-vivo metabolism speed and the like in biopharmaceutics. The reported preparation method for improving the water solubility of ursolic acid is mainly a polymer solid dispersion method, and a large amount of polymer is added while the water solubility and the dissolution rate are improved, so that the volume of the final preparation form is increased, and the stability of the final preparation form is reduced.
Disclosure of Invention
The invention aims to improve the water solubility of ursolic acid, overcome the defects that the volume of a final preparation form is increased due to the addition of a large amount of polymers in a polymer solid dispersion, and the stability of the polymer is reduced due to the hygroscopicity of the polymers, and provide a co-amorphous compound for improving the water solubility of the ursolic acid and a preparation process thereof by adopting a drug-drug co-amorphous system.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation process of a co-amorphous compound for improving the water solubility of ursolic acid is characterized by comprising the following steps: which comprises the following steps:
1) Adding ursolic acid into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain ursolic acid alcoholic solution;
2) Adding quercetin into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain quercetin alcoholic solution;
3) Pouring the quercetin alcohol solution into the ursolic acid alcohol solution according to the mass ratio of the ursolic acid to the quercetin of 1.02-0.2, uniformly mixing, performing rotary evaporation until the ethanol is completely volatilized, and then filling the product into a sealed bag for storage to obtain the co-amorphous compound.
The water bath heating in the step 1) is carried out at the temperature of 85-95 ℃ for 15-20min;
the concentration of the ursolic acid alcoholic solution in the step 1) is 1g/60mL.
The water bath heating in the step 2) is carried out at the temperature of 45-55 ℃ for 20-25min;
the concentration of the lacustrine alcoholic solution in the step 2) is 0.02-0.2g/140mL.
And step 3), the mass ratio of the ursolic acid to the quercetin is 1.
The ursolic acid-quercetin co-amorphous compound prepared by the invention has stable property, and provides a new preparation process for improving the water solubility of pentacyclic triterpenoid compounds such as ursolic acid and the like. In the preparation method, a grinding method and a solvent method are tried, and the solvent method is selected for preparation because the grinding method has poor effect; in the aspect of solvent selection, the invention adopts methanol and ethanol for dissolution, the ethanol has almost no toxicity and better solubility to ursolic acid, so the ethanol is selected as the solvent; in the preparation proportion, different mass ratios of ursolic acid to quercetin are selected, and finally, when the mass ratio of the ursolic acid to the quercetin is 20 in a solvent method, the water solubility of the ursolic acid is improved to 8.36mg/L from the original 3.96 mg/L, and the preparation is characterized and shown to be in an amorphous compound state through powder X-ray diffraction (PXRD) spectrum analysis and Fourier transform infrared spectroscopy (FTIR) analysis.
The invention has the beneficial effects that: the invention uses two active medicinal components, namely ursolic acid and quercetin, as a method for preparing a medicament-medicament amorphous system, and quercetin is used as a ligand (co-former), and a stable amorphous compound is formed with the ursolic acid by utilizing the glassy state forming capability of the quercetin, so that the water solubility of the ursolic acid is increased, and the oral absorption and the medicinal effect of the ursolic acid are improved. The method is simple and easy to implement, excessive carrier components are not added in the prepared compound, the defects that the volume of the final dosage form is increased due to the addition of a large amount of polymers in the polymer solid dispersion, and the stability of the polymer is reduced due to the hygroscopicity are overcome, and the water solubility of the ursolic acid is improved.
Drawings
FIG. 1 is a PXRD pattern of example 6, wherein A is ursolic acid monomer, B is quercetin monomer, C is ursolic acid-quercetin co-amorphous complex prepared by milling, and D is ursolic acid-quercetin complex prepared by solvent method;
FIG. 2 is FTIR chart of ursolic acid of example 6;
FIG. 3 is a graph of quercetin FTIR of example 6;
FIG. 4 is a FTIR profile of ursolic acid-quercetin co-amorphous complex prepared by the solvent method of example 6 (1;
fig. 5 is a graph of FTIR of ursolic acid-quercetin complex (1.
Detailed Description
The invention is described in further detail below with reference to the following figures and detailed description:
example 1
Drawing of ursolic acid standard curve
Precisely weighing ursolic acid standard 10 mg, and dissolving in 100 ml volumetric flask with absolute ethyl alcohol to obtain 0.1 mg/ml ursolic acid standard solution. Precisely sucking ursolic acid standard solutions 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1 ml, 1.1 ml, 1.2 ml and 1.3 ml into a test tube with a plug, heating in a water bath kettle to volatilize a solvent, adding 5% of vanillin-glacial acetic acid 0.5 ml, 1.2 ml of perchloric acid, heating in a water bath at 60 ℃ for 15 minutes, taking out the ice bath for 5 minutes, adding ethyl acetate 4 ml into the test tube, shaking up, and measuring the absorbance at the wavelength of 550 nm. The standard curve is drawn by taking the content of the ursolic acid as an abscissa and the absorbance of the ursolic acid as an ordinate. The standard curve equation is y =9.51x-0.0348, r =0.999.
Example 2
Determination of solubility of Ursolic acid in Water
Take ursolic acid standard 0.1 g in 500ml beaker, add 300ml distilled water, heat in 60 ℃ water bath for 15 minutes, stir with glass rod continuously. And after 15 minutes, putting the beaker into a 90% power ultrasonic instrument for carrying out ultrasonic treatment for 10 minutes, and after the ultrasonic treatment is finished, putting the beaker into a 60 ℃ water bath kettle for heating for 15 minutes. And finally, performing rotary evaporation on the heated solution until the volume of the solution is about 50ml, taking out the solution for suction filtration, and measuring the filtrate to obtain the required ursolic acid aqueous solution. The absorbance was measured at a wavelength of 550nm and was 0.342, and the water solubility was 3.96 mg/L in terms of conversion.
Example 3
Solvent method for preparing ursolic acid-quercetin co-amorphous compound
Taking 5 beakers of 100 ml, respectively placing precisely weighed ursolic acid standard 1g in each beaker, adding 60ml absolute ethyl alcohol, heating in a water bath kettle at 90 ℃ in a water bath for 15 minutes without stirring until the ursolic acid is completely dissolved to obtain the ursolic acid alcohol solution.
Adding precisely weighed quercetin standard substances of 0.02 g, 0.025 g, 0.05 g, 0.1 g and 0.2g into 5 beakers of ml, respectively, adding anhydrous ethanol of 140ml, heating in water bath at 50 ℃ for 20 minutes, and stirring continuously until the quercetin is completely dissolved to obtain a quercetin alcohol solution.
Respectively pouring ursolic acid alcohol solution into quercetin alcohol solution dissolved with 0.02 g, 0.025 g, 0.05 g, 0.1 g and 0.2g, continuously stirring in a beaker by using a glass rod for 10 minutes, respectively pouring the mixed solution into evaporation bottles for rotary evaporation until the ethanol is completely volatilized, scraping off the solids in the bottles by using a key, and filling into a sealed bag to obtain the ursolic acid-quercetin amorphous compound.
Example 4
Preparation of ursolic acid-quercetin compound by physical grinding method
0.1 g, 0.2g, 0.3 g, 0.4 g, and 0.5 g quercetin were placed in 5 mortar, and 1g ursolic acid was added to each mortar. 10 ml absolute ethanol is added dropwise to the mortar to which the drug is added and ground with a grinding bar for 1 to 2 hours, during which time the addition is continued after the ethanol has evaporated. Packaging the ground solid in a sealed bag to obtain ursolic acid-quercetin compound.
Example 5
Determination of water solubility of ursolic acid-quercetin compound obtained by solvent method and physical grinding method
0.1 g is taken out from the ursolic acid-quercetin compound with various proportions in the example 4 and is respectively put into a 500ml beaker, 300ml water is added to carry out water bath heating in a water bath kettle at 60 ℃ for 15 minutes, and the stirring is carried out without using a glass rod; and after 15 minutes, putting the beaker into a 90% power ultrasonic instrument for ultrasonic treatment for 10 minutes, and after the ultrasonic treatment is finished, putting the beaker into a 60 ℃ water bath kettle for heating for 15 minutes. And pouring the heated solution into a rotary evaporation bottle for rotary evaporation, rotating to about 50ml to ensure that the solution is in a saturated state, taking out the solution for filtration, and measuring the volume of the filtrate to be the volume of the compound aqueous solution.
10 ml to 50ml test tubes are respectively taken out from the solution prepared in example 3, heated and evaporated to dryness in a water bath kettle, 5% vanillin-glacial acetic acid 0.5 ml is added, 1.2 ml perchloric acid is added, the solution is bathed for 15 minutes at 60 ℃, the solution after water bath is quickly placed into ice water to be iced for 5 minutes to stop the reaction, the solution after ice bath is taken out and respectively added with 4 ml ethyl acetate, and the absorbance is measured at the wavelength of 550nm after the solution after ice bath is evenly shaken.
The water solubility measurements were as follows:
the ursolic acid-quercetin co-amorphous compound prepared by the solvent method has the mass ratio of 1:0.02, 1:0.025, 1:0.05, 1:0.1, and water solubility of 4.20, 3.17, 8.36, 2..73, and 1.68: mg/L respectively, wherein the water solubility of the compound prepared by the ursolic acid-quercetin mass ratio of 1:0.05 is the highest and is 2.11 times of that of monomeric ursolic acid (the water solubility of 3.96 mg/L).
The mass ratio of the ursolic acid to the quercetin is 1.1, 1, 0.2, 1, 0.3, 1, 0.4 and 1, and the water solubility of the ursolic acid-quercetin compound prepared by the grinding method is respectively 3.76, 3.95, 3.47, 2.71 and 1.68 mg/L, wherein the water solubility of the compound prepared by the ursolic acid-quercetin mass ratio is 1.
The effect of the ursolic acid-quercetin co-amorphous compound prepared by the solvent method is better than that of the grinding method.
Example 6
Characterization of ursolic acid-quercetin complex prepared by the milling method in example 3 (ursolic acid-quercetin mass ratio of 1.05) and ursolic acid-quercetin co-amorphous complex prepared by the solvent method in example 4 (ursolic acid-quercetin mass ratio of 1.
(1) Powder X-ray diffraction (PXRD) pattern analysis
The test selects Cu target (40 kV,40 mV), 2 theta angle, step scan 0.026 degree/step, scan range 5.00 degree-80.00 degree, each step stay time 36.465 s, scan speed 4 degree/min. Separately detecting ursolic acid monomer, quercetin monomer, ursolic acid-quercetin compound prepared by grinding method, and ursolic acid-quercetin co-amorphous compound prepared by solvent method, wherein corresponding PXRD diagram is shown in figure 1.
The PXRD spectrum result shows that the ursolic acid diffraction peak is sharp, and has a plurality of strong crystal diffraction peaks from 5.01 degrees to 16.4 degrees, the quercetin diffraction peak is sharp, and has a plurality of strong crystal diffraction peaks from 5.01 degrees to 27.9 degrees; the diffraction peak of the ursolic acid-quercetin compound prepared by the grinding method is sharp, and a plurality of strong crystallization diffraction peaks exist between 5.01 degrees and 25.3 degrees, which indicates that the crystal state of the ursolic acid is not changed by simple physical mixing; in the spectrum of the ursolic acid-quercetin co-amorphous complex prepared by the solvent method, the diffraction peak of the complex is relatively rough and blunt, but a plurality of obvious diffraction peaks of the ursolic acid and the quercetin disappear, which indicates that the ursolic acid and the quercetin possibly form an amorphous state to coexist.
(2) Fourier transform Infrared Spectroscopy (FTIR) analysis
FTIR is measured by a KBr tabletting method, and after a sample and KBr are mixed and tabletted in a dry environment, the resolution is 32 cm-1,4 000-400 cm-1 full spectrum scanning. Respectively detecting ursolic acid monomer, quercetin monomer, ursolic acid-quercetin compound prepared by grinding method, and ursolic acid-quercetin co-amorphous compound prepared by solvent method.
Fig. 2 shows the scanning results of ursolic acid monomers, wherein 2 free hydroxyl groups 3448,1 carbonyl groups 1716, 1701 is the olefinic site, and 9 groups CH2 are at 2952 (signal intensity).
The scanning results of quercetin monomers are shown in fig. 3, wherein 5 free hydroxyl groups 3385 (strong signal), 1 carbonyl group 1654,2 have benzene rings (1617, 1512).
The scanning results of the ursolic acid-quercetin co-amorphous complex prepared by the solvent method (1.05) are shown in fig. 4, and the observed co-amorphous complex hydroxyl signal shifts to the right slightly to 3447, presumably due to the fact that the free hydroxyl group is used as a proton donor to participate in hydrogen bond formation to cause shift, and the found ursolic acid carbonyl shifts to the left slightly to 1717 while the quercetin carbonyl does not shift, still at 1654, but the signal is weaker due to the smaller proportion. The signals of the two benzene rings are weakened, and it is presumed that the infrared absorption of the benzene rings of the co-amorphous complex may be affected because the hydroxyl groups of quercetin are more abundant than those of ursolic acid and are located around the benzene rings. The distribution of the carbonyl proto groups at 1654, 1716, shifted to 1717 in the co-amorphous complex and the sharp peaks, also suggests that the carbonyl groups also participate in the formation of the dimer structure. The shift in infrared spectra (hydroxyl, carbonyl) indicates that the two molecules presumably form a complex, which is bound by hydrogen bonding.
The scanning spectrum of ursolic acid-quercetin complex (1. Similar to the infrared spectrum of the co-amorphous complex prepared by the solvent method, the hydroxyl group position is different, the hydroxyl signal 3448 of ursolic acid is shifted to the left to 3524, and the hydroxyl signal 3385 of quercetin is shifted to the left to 3421, which shows that the bonding of hydrogen bonds between the co-amorphous complex and the physical complex between ursolic acid and quercetin is obviously different. And (4) conclusion: the infrared spectrum of the compound prepared by the grinding method shows that the hydroxyl signals of the two compounds are separated and do not coincide because hydrogen bonds are not generated between the two molecules to form the compound which is still a single body.
Claims (6)
1. A preparation process of a co-amorphous compound for improving the water solubility of ursolic acid is characterized by comprising the following steps: which comprises the following steps:
1) Adding ursolic acid into anhydrous ethanol, heating in water bath, stirring until completely dissolving to obtain ursolic acid alcohol solution;
2) Adding quercetin into anhydrous ethanol, heating in water bath, stirring, and dissolving completely to obtain quercetin alcoholic solution;
3) Pouring the quercetin alcohol solution into the ursolic acid alcohol solution according to the mass ratio of the ursolic acid to the quercetin of 1.02 or 1.
2. The process for preparing a co-amorphous complex for improving the water solubility of ursolic acid according to claim 1, wherein: the water bath heating in the step 1) is carried out at the temperature of 85-95 ℃ for 15-20min.
3. The process of claim 1, wherein the composition further comprises: the concentration of the ursolic acid alcoholic solution in the step 1) is 1g/60mL.
4. The process of claim 1, wherein the composition further comprises: the water bath heating temperature of the step 2) is 45-55 ℃, and the time is 20-25min.
5. The process of claim 1, wherein the composition further comprises: the concentration of the quercetin alcoholic solution obtained in the step 2) is 0.02-0.2g/140mL.
6. The ursolic acid-quercetin co-amorphous complex obtained according to any one of the preparation processes of claims 1-5.
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Application publication date: 20191227 Assignee: FUJIAN LEEPHICK PHARMACEUTICAL Co.,Ltd. Assignor: LONGYAN University Contract record no.: X2023350000430 Denomination of invention: A Co amorphous Composite and Its Preparation Process for Improving the Water Solubility of Ursolic Acid Granted publication date: 20221025 License type: Common License Record date: 20231115 Application publication date: 20191227 Assignee: TIANJIN CHUNFA BIO-TECHNOLOGY GROUP Co.,Ltd. Assignor: LONGYAN University Contract record no.: X2023350000428 Denomination of invention: A Co amorphous Composite and Its Preparation Process for Improving the Water Solubility of Ursolic Acid Granted publication date: 20221025 License type: Common License Record date: 20231113 |