CN107827724B - Curcumin-2, 5-dihydroxybenzoic acid eutectic crystal and preparation method thereof - Google Patents
Curcumin-2, 5-dihydroxybenzoic acid eutectic crystal and preparation method thereof Download PDFInfo
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- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
Abstract
The invention discloses a curcumin-2, 5-dihydroxybenzoic acid eutectic crystal, which is a eutectic crystal formed by curcumin and 2, 5-dihydroxybenzoic acid; the curcumin-2, 5-dihydroxybenzoic acid self-assembly crystallization method is obtained by self-assembly and volatilization crystallization of curcumin and 2, 5-dihydroxybenzoic acid in a mixed solvent of dichloromethane, ethanol, ether and acetone according to a mass ratio of 1: 0.5-1: 5. The invention also provides a preparation method of the eutectic crystal. The eutectic crystal of the invention has obvious improvement on the aspects of solubility, stability and the like besides inheriting the pharmacological activity of the traditional bulk drug.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystals, and particularly relates to a novel curcumin pharmaceutical co-crystal and a preparation method thereof.
Background
Traditional crystalline drugs exist in a variety of solid forms, such as polymorphs, hydrates, solvates, amorphous forms, and salts. The curative effect of a drug depends greatly on the physicochemical properties of the drug and the selected dosage form, and different solid forms of the drug have influence on the solubility, stability, dissolution rate, bioavailability and the like of the drug.
Crystal engineering provides a wider space for crystal form design of drugs, for example, a supermolecular chemical concept is introduced into crystal design of drug molecules, and a new crystal form-drug cocrystal with specific physicochemical properties is obtained through weak intermolecular force.
Pharmaceutical co-crystals are essentially supramolecular self-assembling systems. During the self-assembly of molecules, intermolecular interactions and steric effects influence the formation of supramolecular networks and thus the crystal formation. In the eutectic system, the interactions between different molecules are mainly hydrogen bonding, pi-pi stacking, van der waals forces and halogen bonding. The pharmaceutical co-crystal is characterized in that the pharmacological activity of the drug is retained, the purpose of modifying the physicochemical property of the drug is achieved, and the formed new crystal can improve the stability of the drug, change the melting point of the drug, improve the solubility of the drug, reduce the hygroscopicity of the drug, slow down the release and dissolution of the drug, improve the mechanical property of the drug and improve the bioavailability of the drug. Therefore, it is of great practical significance to obtain more novel, practical and inventive pharmaceutical co-crystals, especially some water-insoluble drugs.
In many countries around the world, natural drugs are expected in the development of new drugs and used as a lead source for drug discovery and development, and natural botanical drugs have become an important component of the world drug market. Curcumin is a polyphenol substance with small relative molecular mass extracted from a plant of Zingiberaceae, and modern researches find that curcumin has the effects of resisting oxidation, tumors, blood fat, blood sugar and ulcer, protecting liver, resisting myocardial ischemia, depression, bacteria, inflammation, virus and fungi and the like, and can be used for treating cancers, diabetes, coronary heart disease, arthritis, Alzheimer disease (Alzheimer disease) and other chronic diseases.
Curcumin belongs to a fat-soluble compound, is insoluble in water, is easy to oxidize in vitro, is absorbed in vivo less, is metabolized too fast (the elimination half-life period in plasma is only 7.4min), has poor stability, and restricts the wide application of curcumin in clinic. In recent years, dosage forms of curcumin mainly include microemulsions, microspheres, solid dispersions, liposomes, phospholipid complexes, micelles, nanoparticles, cyclodextrin inclusion compounds and the like. For example, chinese patent publication No. 101396334 discloses a lipid carrier for curcumin comprising curcumin; a lipid; surfactants and cosurfactants. Further, as disclosed in chinese patent publication No. 103319508A, a supramolecular compound having a microporous structure using curcumin drug molecules as ligands is disclosed. The above methods, although providing some improvement in dissolution or oral absorption, have disadvantages: (1) the drug loading is low, and a large amount of carrier auxiliary materials are needed for microspheres, nanoparticles, solid dispersions, liposomes and the like, so that the administration volume is increased, and the drug loading is limited; (2) has potential toxicity, such as microemulsion preparation containing a large amount of surfactant; (3) the preparation process may cause curcumin degradation, for example, phospholipid complex needs to carry out complex reaction between the drug and phospholipid at a certain temperature and remove the solvent.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a curcumin-2, 5-dihydroxybenzoic acid eutectic (also called curcumin eutectic or eutectic for short).
The second purpose of the invention is to provide a preparation method of the curcumin-2, 5-dihydroxy benzoic acid eutectic crystal; the aim is to obtain the said co-crystals stably.
A curcumin-2, 5-dihydroxybenzoic acid eutectic is formed by curcumin and 2, 5-dihydroxybenzoic acid.
Through a great deal of research, the inventor originally discovers that the curcumin pharmaceutical co-crystal can be obtained through intermolecular hydrogen bonding action by taking curcumin as a co-crystal pharmaceutical active ingredient (API) and 2, 5-dihydroxybenzoic acid as a precursor. The eutectic provided by the invention is beneficial to improving the solubility, dissolution rate and stability of curcumin and promoting the curcumin to be widely applied in the field of medicines.
The Active Pharmaceutical Ingredient (API) used in the invention is curcumin with a chemical name of (1E, 6E) -1, 7-bis (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione and a molecular formula of: c21H20O6The structural formula is shown as formula 1. In the invention, 2, 5-dihydroxy benzoic acid is used as a eutectic precursor, and the structural formula of the eutectic precursorAs shown in equation 2.
Preferably, the curcumin-2, 5-dihydroxybenzoic acid eutectic crystal is prepared from the following components in a mass ratio of 1: 0.5-1: 5 curcumin and 2, 5-dihydroxybenzoic acid are self-assembled to obtain the curcumin-2-dihydroxybenzoic acid self-assembly.
Preferably, the curcumin-2, 5-dihydroxybenzoic acid eutectic is obtained by self-assembly and volatilization crystallization in a mixed solvent of at least two of dichloromethane, ethanol, diethyl ether and acetone. The eutectic crystal is prepared by dissolving curcumin and 2, 5-dihydroxybenzoic acid in the mass ratio in the mixed solvent for self-assembly; and then volatilizing and crystallizing the self-assembled reaction liquid to obtain the eutectic.
Preferably, the curcumin-2, 5-dihydroxybenzoic acid eutectic has main characteristic peaks at diffraction angles 2 theta of 7.8 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 24 degrees +/-0.2 degrees, 27.9 degrees +/-0.2 degrees and 35.9 degrees +/-0.2 degrees under powder X-ray diffraction.
The study also finds that the curcumin-2, 5-dihydroxy benzoic acid eutectic also has characteristic peaks at diffraction angles 2 theta of 8.8 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 14.3 degrees +/-0.2 degrees, 21.0 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 29.4 degrees +/-0.2 degrees, 31.5 degrees +/-0.2 degrees, 32.1 degrees +/-0.2 degrees, 36.8 degrees +/-0.2 degrees and 39.6 degrees +/-0.2 degrees under the powder X-ray diffraction.
Preferably, the melting point of the curcumin-2, 5-dihydroxybenzoic acid eutectic is 156 +/-0.2 ℃. The curcumin-2, 5-dihydroxy benzoic acid eutectic is tested by a differential scanning calorimeter, and the melting point is 156 ℃.
The invention also provides a preparation method of the curcumin-2, 5-dihydroxy benzoic acid eutectic, which comprises the following steps:
step (1): mixing the components in a mass ratio of 1: self-assembling curcumin and 2, 5-dihydroxybenzoic acid in a crystallization solvent at a ratio of 0.5-1: 5;
the crystallization solvent is a mixed solvent of at least two of dichloromethane, ethanol, diethyl ether and acetone;
the volume ratio of the weight of the curcumin and the 2, 5-dihydroxybenzoic acid to the crystallization solvent is 10-25 mg/mL;
step (2): and (2) volatilizing, crystallizing, washing and drying the solution obtained in the step (1) to obtain the curcumin-2, 5-dihydroxybenzoic acid eutectic.
The present inventors have found through extensive studies that the co-crystal can be stably obtained by controlling the mass ratio of curcumin to 2, 5-dihydroxybenzoic acid and the concentration in the mixed solvent (crystallization solvent) in the mixed solvent system.
Preferably, the crystallization solvent is dichloromethane or acetone, and optionally contains ethanol and diethyl ether.
Preferably, in the crystallization solvent, the volume part of dichloromethane is 1-4 parts; 1-4 parts of acetone by volume; the volume part of the ethanol is less than or equal to 2 parts; the volume part of the diethyl ether is less than or equal to 2 parts.
Preferably, the method comprises the following steps: in the step (1), the temperature in the self-assembly process is 20-35 ℃.
And under the self-assembly temperature, the preferable self-assembly time is 4-12 hours.
In the self-assembly process of the present invention, the self-assembly is preferably performed under closed conditions, which helps to avoid premature volatilization of the solvent.
Preferably, the method comprises the following steps: in the step (2), the temperature of volatilization and crystallization is room temperature. The room temperature is, for example, 20 to 35 ℃.
In the invention, the solution obtained by self-assembly in the step (1) is slowly volatilized at room temperature to precipitate the eutectic crystal. The crystallization solvent selected by the invention has a low boiling point, and crystals can be crystallized in the solvent volatilization process.
The time for volatilization and crystallization is preferably 24 to 48 hours.
In the step (2), the crystallization solvent having a temperature lower than room temperature (for example, lower than 15 ℃) is used as the washing solvent in the washing process.
In the present invention, the washed product is dried by a conventional method for removing the crystallization solvent, for example, vacuum drying.
The curcumin organic pharmaceutical co-crystal is prepared by taking dichloromethane, ethanol, diethyl ether and acetone as mixed solvents and adopting a solvent room temperature volatilization method. The preparation method comprises the following steps:
1) adding curcumin and 2, 5-dihydroxybenzoic acid in a mass ratio of 1: 0.5-1: 5 and at least two mixed solvents of dichloromethane, ethanol, diethyl ether and acetone in a volume ratio of 1-4: 1-2: 1-4 into a transparent glass vial, wherein the solid content of a reaction system is 10-25 mg/mL;
2) placing the transparent glass vial on an oscillator, and oscillating for 4-12 hours at a constant temperature of 20-35 ℃;
3) after the oscillation is stopped, placing the transparent glass vial in a room temperature environment for 24-48 hours, and then precipitating needle crystals;
4) filtering, washing the filter cake, and vacuum drying to obtain curcumin organic pharmaceutical co-crystal.
Curcumin has effects of resisting oxidation, resisting tumor, reducing blood lipid, lowering blood sugar, resisting ulcer, protecting liver, resisting myocardial ischemia, resisting depression, resisting bacteria, diminishing inflammation, resisting virus and resisting fungi, and can be used for treating cancer, diabetes, coronary atherosclerotic heart disease, arthritis, Alzheimer disease (Alzheimer disease) and other chronic diseases. Curcumin is gradually proved to have wide development space in the aspects of resisting tumor, oxidation and atherosclerosis, resisting coagulation, reducing blood fat, resisting mutation, protecting liver and the like, and the development prospect is very attractive. The invention originally selects 2, 5-dihydroxy benzoic acid as a precursor, and the formed eutectic keeps the good drug effect performance of curcumin.
Compared with the existing method for improving the property of the active ingredient of the medicament, the preparation of the eutectic is more operable, so that ionizable groups do not exist in the structure of the active molecule of the medicament, and the eutectic can be prepared through process improvement, thereby achieving the purpose of improving the property of the medicament.
Advantageous effects
The eutectic crystal prepared by the invention inherits the pharmacological activity of curcumin and obviously improves the aspects of solubility, stability and the like of the curcumin.
Drawings
FIG. 1 is a PXRD diagram of curcumin and 2, 5-dihydroxybenzoic acid and their co-crystals, wherein: CU is curcumin; DHBA is 2, 5-dihydroxybenzoic acid; CU/DHBA is curcumin-2, 5-dihydroxy benzoic acid eutectic;
FIG. 2 is an HPLC chart of curcumin and 2, 5-dihydroxybenzoic acid and their co-crystals, wherein: FIG. 2a is Curcumin (CU); FIG. 2b is 2, 5-dihydroxybenzoic acid (DHBA); FIG. 2c is curcumin-2, 5-dihydroxybenzoic acid eutectic (CU/DHBA);
FIG. 3 is a DSC chart of curcumin, 2, 5-dihydroxybenzoic acid and their co-crystals tested in nitrogen atmosphere, wherein: figure 3a is curcumin; FIG. 3b is 2, 5-dihydroxybenzoic acid; FIG. 3c is curcumin-2, 5-dihydroxybenzoic acid eutectic (CU/DHBA);
FIG. 4 is a graph showing the relationship between the absorbance of curcumin solid powder and curcumin-2, 5-dihydroxybenzoic acid eutectic compound with the change of illumination time.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The instrument for detecting the pharmaceutical cocrystal structure comprises the following components:
an X-ray powder diffractometer manufactured by Shimadzu corporation of Japan, having a model of XRD-6000X, Cu-K (α), tube voltage 40kV, tube current 40mA, scanning speed 2 °/min.
2. High performance liquid chromatograph, Shanghai Lai Rui scientific instruments GmbH, type Agilent 1260, with detection wavelength of 320 nm; the column temperature is 30 ℃; the flow rate is 1.0 mL/min; the mobile phase was acetonitrile/2% acetic acid solution (45/55).
3. A differential scanning calorimeter, a TA company, USA, model Q20, adopts nitrogen atmosphere, and the heating rate is 10 ℃/min.
3. Ultraviolet visible spectrophotometer, model Blue Star, manufactured by Redbertaceae instruments Inc. of Beijing.
4. The test method of the light stability experiment comprises the following steps:
respectively putting equal amount of curcumin solid powder and curcumin-2, 5-dihydroxybenzoic acid eutectic compound in 4 transparent self-sealing bags, sealing, and spreading in white porcelain dish. After the indoor illumination experiment is finished, dissolving a sample by using absolute ethyl alcohol, and measuring the absorbance of the sample at 425nm by using a 1cm quartz cuvette as an absorption cell and absolute ethyl alcohol as a reference.
The transparent glass vial used in the present invention had a capacity of 20mL and good sealing properties.
Example 1
The eutectic is synthesized by curcumin and 2, 5-dihydroxy benzoic acid through a solvent room temperature volatilization method:
the reactants are as follows: feeding 2, 5-dihydroxy benzoic acid in the mass ratio of 1 to 1. 20.00mg of curcumin and 20.00mg of 2, 5-dihydroxybenzoic acid were accurately weighed with an electronic analytical balance and placed in a transparent glass vial.
Dissolving the raw material medicines:
accurately transferring 1mL of dichloromethane, 2mL of ether and 1mL of acetone by using a liquid transfer gun, placing the mixture into a glass vial, stirring the mixture on a magnetic stirrer for 4 hours at the temperature of 25 ℃, taking out a stirrer, adding a layer of tinfoil between a bottle cap and a bottle body to increase the sealing property, and screwing the mixture tightly.
Solvent room temperature volatilization method:
placing the glass vial in a room temperature environment, slightly sealing with tinfoil to prevent foreign matters from entering the culture solution, standing for 30 hours until the solution is saturated, and separating out crystals, wherein orange needle-like transparent crystals, namely curcumin eutectic, are obtained along with continuous volatilization of the solvent.
As can be seen from FIG. 1, the characteristic diffraction peaks of CU/DHBA at 7.8 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 24 degrees +/-0.2 degrees, 27.9 degrees +/-0.2 degrees and 35.9 degrees +/-0.2 degrees are obviously different from those of bulk drugs (CU and DHBA), and meanwhile, the main characteristic peaks in CU and DHBA disappear in the eutectic compound, which indicates that the CU and DHBA form the eutectic compound with a new crystal form structure through hydrogen bond interaction.
As can be seen from FIG. 2c, chromatographic peaks of CU and DHBA appeared simultaneously in HPLC of CU/DHBA, and the peak-off time was consistent with that of CU and DHBA, respectively. On the other hand, in FIG. 2c, the ratio of peak areas of the peaks of the chromatogram of CU and DHBA is consistent with the ratio of the amounts of the substances of CU and DHBA (CU: DHBA), which indicates that CU and DHBA form a eutectic compound through intermolecular interaction.
As can be seen from FIG. 3, the melting point of CU is 186 ℃, the melting point of DHBA is 206 ℃, and the melting point of CU/DHBA (156 ℃) is obviously different from that of the bulk drug, which indicates that CU and DHBA form a eutectic compound through self-assembly.
As can be seen from fig. 4, the absorbance of the curcumin solid powder began to slightly decrease after the indoor light test for 3 consecutive days. Compared with the curcumin-2, 5-dihydroxy benzoic acid eutectic compound, the absorbance of the curcumin-2, 5-dihydroxy benzoic acid eutectic compound is basically unchanged after continuous indoor illumination experiments for four weeks, and the curcumin-2, 5-dihydroxy benzoic acid eutectic compound is proved to have better light stability.
The solubility of the curcumin eutectic and curcumin-2, 5-dihydroxybenzoic acid eutectic in water at 25 ℃ is respectively 0.38 mu g/mL and 10.6 mu g/mL measured by an HPLC method, and the solubility of the curcumin eutectic compound is improved by about 28 times.
Example 2
The eutectic is synthesized by curcumin and 2, 5-dihydroxy benzoic acid through a solvent room temperature volatilization method:
the reactants are fed according to the mass ratio of curcumin to 2, 5-dihydroxy benzoic acid being 1 to 5. 10.00mg of curcumin and 50.00mg of 2, 5-dihydroxybenzoic acid were accurately weighed with an electronic analytical balance and placed in a transparent glass vial.
Dissolving the raw material medicines:
accurately transferring 1mL of dichloromethane, 2mL of ether and 1mL of acetone by using a liquid transfer gun, placing the mixture into a glass vial, stirring the mixture on a magnetic stirrer for 4 hours at the temperature of 25 ℃, taking out a stirrer, adding a layer of tinfoil between a bottle cap and a bottle body to increase the sealing property, and screwing the mixture tightly.
Solvent room temperature volatilization method:
placing the small glass bottle in a room temperature environment, slightly sealing the small glass bottle by tinfoil to prevent foreign matters from entering the culture solution, standing for 30 hours until the solution is saturated, and separating out crystals, wherein orange needle-shaped transparent crystals, namely the curcumin-2, 5-dihydroxybenzoic acid pharmaceutical co-crystal, are obtained along with the continuous volatilization of the solvent.
Example 3
The eutectic is synthesized by curcumin and 2, 5-dihydroxy benzoic acid through a solvent room temperature volatilization method:
the reactants are fed according to the mass ratio of curcumin to 2, 5-dihydroxy benzoic acid being 1 to 1. 20.00mg of curcumin and 20.00mg of 2, 5-dihydroxybenzoic acid were accurately weighed with an electronic analytical balance and placed in a transparent glass vial.
Dissolving the raw material medicines:
accurately transferring 2mL of dichloromethane, 1mL of ethanol and 1mL of acetone by using a liquid transfer gun, placing the mixture into a glass vial, stirring the mixture on a magnetic stirrer for 4 hours at the temperature of 25 ℃, taking out a stirrer, adding a layer of tinfoil between a bottle cap and a bottle body to increase the sealing property, and screwing the mixture tightly.
Solvent room temperature volatilization method:
placing the small glass bottle in a room temperature environment, slightly sealing the small glass bottle by tinfoil to prevent foreign matters from entering the culture solution, standing for 30 hours until the solution is saturated, and separating out crystals, wherein orange needle-shaped transparent crystals, namely the curcumin-2, 5-dihydroxybenzoic acid pharmaceutical co-crystal, are obtained along with the continuous volatilization of the solvent.
Comparative example 1
The eutectic is synthesized by curcumin and 2, 5-dihydroxy benzoic acid through a solvent room temperature volatilization method:
the reactants are fed according to the mass ratio of curcumin to 2, 5-dihydroxy benzoic acid being 1 to 10. 10.00mg of curcumin and 100.00mg of 2, 5-dihydroxybenzoic acid were accurately weighed with an electronic analytical balance and placed in a transparent glass vial.
Dissolving the raw material medicines:
accurately transferring 2mL of dichloromethane, 2mL of diethyl ether and 1.5mL of acetone by using a liquid transfer gun, placing the mixture into a glass vial, stirring the mixture on a magnetic stirrer for 4 hours at the temperature of 25 ℃, taking out a stirrer, adding a layer of tinfoil between a bottle cap and a bottle body to increase the sealing property, and screwing the mixture tightly.
Solvent room temperature volatilization method:
placing the glass vial in a room temperature environment, slightly sealing the glass vial by tinfoil to prevent foreign matters from entering a culture solution, standing for 30 hours, obtaining brownish red powder along with the continuous volatilization of a solvent, determining that a diffraction characteristic peak of the powder is completely consistent with that of curcumin through PXRD test, determining that a product is curcumin, and failing to obtain a eutectic compound.
Comparative example 2
The eutectic is synthesized by curcumin and 2, 5-dihydroxy benzoic acid through a solvent room temperature volatilization method:
the reactants are fed according to the mass ratio of curcumin to 2, 5-dihydroxy benzoic acid being 1 to 1. 20.00mg of curcumin and 20.00mg of 2, 5-dihydroxybenzoic acid were accurately weighed with an electronic analytical balance and placed in a transparent glass vial.
Dissolving the raw material medicines:
accurately transferring 4mL of dichloromethane by using a liquid transfer gun, placing the dichloromethane into a glass small bottle, stirring the dichloromethane on a magnetic stirrer for 4 hours at the temperature of 25 ℃, taking out a stirrer, adding a layer of tinfoil between a bottle cap and a bottle body to increase the sealing property, and screwing the tinfoil tightly.
Solvent room temperature volatilization method:
placing the glass vial in a room temperature environment, slightly sealing the glass vial by tinfoil to prevent foreign matters from entering a culture solution, standing for 30 hours, obtaining brownish red powder along with the continuous volatilization of a solvent, determining that a diffraction characteristic peak of the powder is completely consistent with that of curcumin through PXRD test, determining that a product is curcumin, and failing to obtain a eutectic compound.
Compared with the comparative example 2, the difference is only that the single ethanol, ether and acetone are adopted to replace the dichloromethane, and the experimental result is similar to the comparative example 2, and the curcumin-2, 5-dihydroxy benzoic acid eutectic can not be obtained.
Claims (5)
1. A curcumin-2, 5-dihydroxy benzoic acid eutectic crystal is characterized in that: is a eutectic crystal formed by curcumin and 2, 5-dihydroxy benzoic acid;
the curcumin-2, 5-dihydroxybenzoic acid self-assembly solvent is obtained by self-assembling curcumin and 2, 5-dihydroxybenzoic acid in a mass ratio of 1: 0.5-1: 5 in a crystallization solvent;
the crystallization solvent is dichloromethane and acetone, and selectively contains ethanol and diethyl ether;
wherein the volume part of the dichloromethane is 1-4 parts; 1-4 parts of acetone by volume; the volume part of the ethanol is less than or equal to 2 parts; the volume part of the diethyl ether is less than or equal to 2 parts; wherein, the volume parts of the ethanol and the diethyl ether are not 0 part at the same time;
the curcumin-2, 5-dihydroxybenzoic acid eutectic crystal has a diffraction angle 2 theta of 7.8 under powder X-ray diffraction o±0.2 o、15.8 o±0.2 o、17.5 o±0.2 o、24 o±0.2 o、27.9 o±0.2 o、35.9 o±0.2 oHas a main characteristic peak; also at a diffraction angle 2 theta of 8.8 o±0.2 o、13.9 o±0.2 o、14.3 o±0.2 o、21.0 o±0.2 o、21.8 o±0.2 o、29.4 o±0.2 o、31.5 o±0.2 o、32.1 o±0.2 o、36.8 o±0.2 o、39.6 o±0.2 oHas characteristic peaks.
2. A curcumin-2, 5-dihydroxybenzoic acid eutectic of claim 1, characterized in that: the melting point of the curcumin-2, 5-dihydroxybenzoic acid eutectic is 156oC±0.2 oC。
3. The method for preparing curcumin-2, 5-dihydroxybenzoic acid eutectic crystal according to any one of claims 1 to 2, characterized in that:
step (1): self-assembling curcumin and 2, 5-dihydroxybenzoic acid in a mass ratio of 1: 0.5-1: 5 in a crystallization solvent;
the crystallization solvent is dichloromethane and acetone, and selectively contains ethanol and diethyl ether;
wherein the volume part of the dichloromethane is 1-4 parts; 1-4 parts of acetone by volume; the volume part of the ethanol is less than or equal to 2 parts; the volume part of the diethyl ether is less than or equal to 2 parts; wherein, the volume parts of the ethanol and the diethyl ether are not 0 part at the same time;
the volume ratio of the weight of the curcumin and the 2, 5-dihydroxybenzoic acid to the crystallization solvent is 10-25 mg/mL;
step (2): and (2) volatilizing, crystallizing, washing and drying the solution obtained in the step (1) to obtain the curcumin-2, 5-dihydroxybenzoic acid eutectic.
4. The method for preparing curcumin-2, 5-dihydroxybenzoic acid eutectic of claim 3, wherein: in the step (1), the temperature in the self-assembly process is 20-35 DEGoC; the time is 4-12 hours.
5. The method for preparing curcumin-2, 5-dihydroxybenzoic acid eutectic of claim 3, wherein: in the step (2), the volatilization crystallization temperature is room temperature;
the speed of volatilization and crystallization is 24-48 hours;
in the step (2), the crystallization solvent with the temperature lower than room temperature is adopted as the washing solvent in the washing process.
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| CN109453148A (en) * | 2018-12-12 | 2019-03-12 | 湖南湘源美东医药科技有限公司 | A kind of curcumin eutectic composition and preparation method thereof |
| CN109432055B (en) * | 2018-12-12 | 2021-11-23 | 湖南湘源美东医药科技有限公司 | Composite nano-particles of curcumin eutectic/piperine coated by polymer, preparation thereof and application thereof in sustained-release pharmaceutical preparation |
| CN110668932B (en) * | 2019-09-10 | 2023-11-03 | 刘湖 | Co-crystal, preparation method, pharmaceutical composition containing co-crystal and application |
| CN113817012B (en) * | 2021-09-16 | 2022-11-18 | 国家卫生健康委科学技术研究所 | Progesterone eutectic crystal and preparation method and application thereof |
| WO2023109855A1 (en) * | 2021-12-15 | 2023-06-22 | 湖南湘源美东医药科技有限公司 | Curcumin cocrystal, preparation method therefor, and use thereof as drug or in pharmaceutical preparation |
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| WO2012138907A2 (en) * | 2011-04-05 | 2012-10-11 | Translational Genomics Research Institute | Solid forms of curcumin |
| CN102702092B (en) * | 2012-06-01 | 2013-10-23 | 吉林大学 | Eutectic of two curcumin organic medicaments and preparation method thereof |
| CN103319508B (en) * | 2013-07-09 | 2016-06-08 | 长春市力诚必成新药科技开发有限责任公司 | A kind of be part with drug molecule microcellular structure super molecular compound and preparation method thereof |
| CN104193627B (en) * | 2014-08-18 | 2016-05-25 | 江苏正大清江制药有限公司 | A kind of ambroxol and PCA pharmaceutical co-crystals and preparation method thereof |
| CN105399664A (en) * | 2015-12-11 | 2016-03-16 | 吉林大学珠海学院 | Deferiprone pharmaceutical cocrystal with 2,5-dihydroxybenzoic acid as precursor and preparation method thereof |
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