CN107827724A - Dihydroxybenzoic acid cocrystal of curcumin 2,5 and preparation method thereof - Google Patents
Dihydroxybenzoic acid cocrystal of curcumin 2,5 and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—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
- 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
It is curcumin and 2 the invention discloses a kind of dihydroxybenzoic acid cocrystal of curcumin 2,5, the eutectic that 5 dihydroxy-benzoic acids are formed；Its by mass ratio be 1: 0.5~1: 5 curcumin and 2,5 dihydroxy-benzoic acids dichloromethane, ethanol, ether and acetone in the mixed solvent self assembly, volatilization crystallization obtain.Present invention also offers the preparation method of described eutectic.Eutectic of the present invention is being inherited outside the pharmacological activity of traditional raw material medicine in itself, and its dissolubility, stability etc. significantly improve.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, and in particular to a kind of novel curcumin pharmaceutical co-crystals and its preparation side
Method.
Background technology
Traditional crystal formation medicine exists in the form of many kinds of solids, as polymorphic, hydrate, solvate, it is amorphous and
Salt etc..The effect of one medicine, is heavily dependent on the physicochemical property of medicine itself and the formulation of selection, and medicine is different
Solid forms have an impact to the solubility of medicine, stability, dissolution rate and bioavilability etc..
Crystal engineering provides broader space for the crystal formation design of medicine, such as introduces the concept of supramolecular chemistry
The crystal design of drug molecule, by weak intermolecular force, obtain having novel crystal forms-medicine of specific physicochemical property common
It is brilliant.
Pharmaceutical co-crystals are substantially a kind of Supramolecular self assembly systems.It is intermolecular mutual during molecular self-assembling
Effect and three-dimensional effect influence the formation of Supramolecular Network, so as to influence the composition of crystal.In eutectic system, different molecular
Between interaction mainly have a hydrogen bond, pi-pi accumulation effect, Van der Waals force and halogen key.The characteristics of pharmaceutical co-crystals, is, retains medicine
While pharmacological activity itself, the purpose for modifying its physicochemical properties is reached, the new crystal of formation can improve medicine
Stability, change its fusing point, improve its dissolubility, reduce its draw it is moist, slow down its release and dissolution rate, improve its mechanicalness
Matter, improve its bioavilability.Therefore, more pharmaceutical co-crystals with novel, practicality and creativeness are obtained with important to show
Sincere justice, particularly some water-insoluble drugs.
Many countries all place hope on natural drug in terms of new drug development in the world, as drug discovery and development
Guide source, natural plant turns into one important part of international drugs in the market.Curcumin is planted from Zingiber
A kind of small polyphenols of relative molecular mass for being extracted in thing, modern study find curcumin have it is anti-oxidant, antitumor,
Reducing blood lipid, hypoglycemic, antiulcer, protection liver, resist myocardial ischemia, be antidepression, antibacterial, anti-inflammatory, antiviral and antimycotic etc. make
With available for treating cancer, diabetes, coronary heart disease, arthritis, Alzheimer's (alzheimer's disease) and other are chronic
Disease.
Curcumin category fat-soluble compound, is insoluble in water, is also oxidized easily in vitro, absorbs less, was metabolized in vivo
It hurry up (elimination half-life period is only 7.4min in blood plasma), stability is poor, constrains extensive use of the curcumin in clinic.In recent years
Come, the formulation on curcumin mainly have micro emulsion, microballoon, solid dispersions, liposome, phosphatide complexes, micella, nanoparticle with
And cyclodextrin inclusion compound etc..Such as the Chinese patent literature of Publication No. 101396334 discloses a kind of lipid load of curcumin
Body, include curcumin；Lipid；Surfactant and cosurfactant.For another example Publication No. 103319508A Chinese patent
Document discloses a kind of microcellular structure super molecular compound using curcumin drug molecule as part.Above method is although dissolving
Or have certain improvement in terms of oral absorption, but still have deficiency：(1) drugloading rate is low, such as microballoon, nanoparticle, solid dispersions, lipid
The a large amount of carrier auxiliary materials of the needs such as body, administered volume increase, are limited drugloading rate；(2) there is genotoxic potential, as microemulsion formulation contains greatly
Measure surfactant；(3) preparation process is possible to cause curcumin to be degraded, as phosphatide complexes need at a certain temperature medicine with
Phosphatide carries out recombination reaction and removes solvent.
The content of the invention
To solve the deficiencies in the prior art, the invention provides a kind of curcumin-DHB eutectic (this hair
Bright also referred to as curcumin eutectic, or referred to as eutectic).
Second purpose of the invention is, there is provided the preparation method of described curcumin-DHB eutectic；
It is intended to stably obtain described eutectic.
A kind of curcumin-DHB eutectic, it is the eutectic that curcumin and DHB are formed.
The present inventor is originally had found by numerous studies, using curcumin as eutectic active constituents of medicine (API),
Using DHB as presoma, can act on obtaining described curcumin pharmaceutical co-crystals by intermolecular hydrogen bonding.This
The eutectic provided is provided, helps to improve curcumin dissolubility and dissolution rate and stability, promotes curcumin in field of medicaments
Extensive use.
The active constituents of medicine (API) used in the present invention is curcumin, and chemical name is double (the 4- hydroxyls of (1E, 6E) -1,7-
Base -3- methoxyphenyls) -1,6- heptadiene -3,5- diketone, molecular formula is：C21H20O6, its structural formula is as shown in Equation 1.The present invention
It is middle as shown in Equation 2 by the use of DHB as eutectic precursor, its structural formula.
Preferably, described curcumin-DHB eutectic, is 1 by mass ratio：0.5~1: 5 turmeric
Element and DHB self assembly obtain.
Further preferably, described curcumin-DHB eutectic, in dichloromethane, ethanol, ether and third
At least two in the mixed solvent self assembly, volatilization crystallization in ketone obtain.Eutectic of the present invention, by the mass ratio
Curcumin and DHB are dissolved in described in the mixed solvent, carry out self assembly；Then by the reaction of self assembly
Liquid obtains described eutectic through the crystallization that volatilizees.
Preferably, described curcumin-DHB eutectic is under powder x-ray diffraction, in the angle of diffraction 2
θ is to have at 7.8 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.5 ° ± 0.2 °, 24 ° ± 0.2 °, 27.9 ° ± 0.2 °, 35.9 ° ± 0.2 °
Main characteristic peak.
Research also found that described curcumin-DHB eutectic is also spreading out under powder x-ray diffraction
The θ of firing angle degree 2 is 8.8 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.3 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.8 ° ± 0.2 °, 29.4 °
There is characteristic peak at ± 0.2 °, 31.5 ° ± 0.2 °, 32.1 ° ± 0.2 °, 36.8 ° ± 0.2 °, 39.6 ° ± 0.2 °.
Preferably, the fusing point of described curcumin-DHB eutectic is 156 DEG C ± 0.2 DEG C.Turmeric
Element-DHB eutectic is tested through differential scanning calorimeter, and its fusing point is 156 DEG C.
Present invention also offers a kind of preparation method of described curcumin-DHB eutectic, including with
Lower step：
Step (1)：It is 1 by mass ratio：0.5~1: 5 curcumin and DHB in recrystallisation solvent from
Assembling；
Described recrystallisation solvent is at least two mixed solvent in dichloromethane, ethanol, ether and acetone；
The volume ratio of the weight and recrystallisation solvent of curcumin and DHB is 10~25mg/mL；
Step (2)：By the solution that step (1) obtains through crystallization, washing, the drying of volatilizing, described curcumin -2,5- is produced
Dihydroxybenzoic acid cocrystal.
The present inventor is had found by numerous studies, under described mixed solvent system, controls curcumin and 2,5- dihydroxy
Yl benzoic acid mass ratio and the concentration in mixed solvent (recrystallisation solvent), described eutectic can be stably obtained.
Preferably, described recrystallisation solvent is dichloromethane, acetone, selectivity includes ethanol and ether.
Preferably, in described recrystallisation solvent, the volume parts of dichloromethane are 1~4 part；The volume parts of acetone are
1~4 part；The volume parts of ethanol are less than or equal to 2 parts；The volume parts of ether are less than or equal to 2 parts.
As preferred：In step (1), the temperature of self assembling process is 20~35 DEG C.
At a temperature of described self assembly, the preferable self assembly time is 4~12 hours.
In self assembling process of the present invention, described self assembly is preferably carried out in confined conditions, helps avoid solvent
Volatilization too early.
As preferred：In step (2), volatilization recrystallization temperature is room temperature.Described room temperature is, for example, 20~35 DEG C.
In the present invention, the solution that step (1) self assembly obtains slowly is volatilized at room temperature, separates out described eutectic.This
It is relatively low to invent the boiling point for the recrystallisation solvent selected, has crystal structure to come out during solvent volatilizees.
The time of volatilization crystallization is preferably 24~48 hours.
In step (2), in washing process, using described recrystallisation solvent of the temperature less than room temperature (for example, less than 15 DEG C)
As cleaning solvent.
In the present invention, the product after washing is dried, dry method can use it is existing remove it is described crystallization it is molten
The method of agent, such as be dried in vacuo.
The curcumin organic pharmaceutical co-crystal of the present invention is mixed solvent from dichloromethane, ethanol, ether and acetone, is used
Solvent room temperature volatility process is prepared.Preferable preparation method, comprises the following steps：
1) it is 1~4: 1~2: 1~2 by the curcumin of mass ratio 1: 0.5~1: 5 and DHB, volume ratio
: at least two mixed solvents in 1~4 dichloromethane, ethanol, ether and acetone, it is added in the lump in clear glass bottle,
The solid contents of reaction system is 10~25mg/mL；
2) clear glass bottle is placed on oscillator, constant temperature oscillation is carried out at 20~35 DEG C 4~12 hours；
3) after vibration stops, clear glass bottle being placed under room temperature environment after placing 24~48 hours has acicular crystal analysis
Go out；
4) filter, wash filter cake and be dried in vacuo, produce curcumin organic pharmaceutical co-crystal.
Curcumin has anti-oxidant, antitumor, reducing blood lipid, hypoglycemic, antiulcer, protects liver, resists myocardial ischemia, anti-suppression
Strongly fragrant, antibacterial, anti-inflammatory, antiviral and antimycotic etc. effect, available for treating cancer, diabetes, coronary heart disease, arthritis, A Erci
Extra large Mo's disease (alzheimer's disease) and other chronic diseases.Curcumin is gradually proved in antitumor, anti-oxidant, anti-artery congee
Sample hardening, anti-freezing, reducing blood lipid, anti-mutation, liver protection etc. have a wide developing space, and development prospect is very tempting.This hair
Bright is originally presoma from DHB, and the eutectic of formation remains the good drug effect performance of curcumin.
In the present invention, compared with the method for existing improvement active constituents of medicine property, the preparation of eutectic has more operability,
It can make ionogen is not present in the structure of pharmaceutical activity molecule, eutectic can also be made by process modification, so as to
Reaching improves the purpose of pharmaceutical properties.
Beneficial effect
Eutectic prepared by the present invention inherits the pharmacological activity of curcumin in itself, and to its dissolubility, stability etc.
It is significantly improved.
Brief description of the drawings
Fig. 1 is that curcumin and the PXRD of DHB and its eutectic scheme, wherein：CU is curcumin；DHBA is
DHB；CU/DHBA is curcumin-DHB eutectic；
Fig. 2 is that curcumin and the HPLC of DHB and its eutectic scheme, wherein：Fig. 2 a are curcumin (CU)；
Fig. 2 b are DHB (DHBA)；Fig. 2 c are curcumin-DHB eutectic (CU/DHBA)；
Fig. 3 is the DSC figures that curcumin and DHB and its eutectic are tested under nitrogen atmosphere, wherein：Figure
3a is curcumin；Fig. 3 b are DHB；Fig. 3 c are curcumin-DHB eutectic (CU/DHBA)；
Fig. 4 is the absorbance of curcumin solid powder and curcumin-DHB cocrystalization compound with illumination
The graph of a relation of time change.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.
The instrument that pharmaceutical co-crystals structure is detected in the present invention is as follows：
1.X ray powder diffractometers, Japanese Shimadzu Corporation's production, model XRD-6000X, Cu-K (α), tube voltage
40kV, tube current 40mA, 2 °/min of sweep speed.
2. high performance liquid chromatograph, Shanghai Lai Rui scientific instrument Co., Ltd, model Agilent 1260, Detection wavelength
320nm；30 DEG C of column temperature；Flow velocity 1.0mL/min；Mobile phase is the acetum (45/55) of acetonitrile/2%.
3. differential scanning calorimeter, TA companies of the U.S., model Q20, the present invention uses nitrogen atmosphere, 10 DEG C of heating rate/
min。
3. ultraviolet-uisible spectrophotometer, Beijing Labtech Instrument Co., Ltd., model Blue Star B.
4. Photostability experiments method of testing：
Take curcumin solid powder and the curcumin-DHB cocrystalization compound of equivalent saturating in 4 respectively
Divided in bright valve bag, after sealing in ceramic whiteware disk.After indoor illumination experiment terminates, with absolute ethyl alcohol sample dissolution, with 1cm stones
English cuvette is absorption cell, absolute ethyl alcohol is reference, determines its absorbance at 425nm.
The clear glass bottle capacity 20mL used in invention, sealing are fine.
Embodiment 1
Eutectic is synthesized by solvent room temperature volatility process using curcumin and DHB：
Reactant presses curcumin：DHB=1: 1 mass ratio feeds intake.Accurately claimed with electronic analytical balance
20.00mg curcumin and 20.00mg DHB are taken, is inserted in clear glass bottle.
The dissolving of bulk drug：
Accurately pipette 1mL dichloromethane, 2mL ether and 1mL acetone with liquid-transfering gun to insert in vial, 25 DEG C of temperature strips
Under part, in being stirred 4 hours on magnetic stirring apparatus, stirrer is taken out, between bottle cap and bottle plus one layer of tinfoil increases sealing, twists
Tightly.
Solvent room temperature volatility process：
Vial is placed in room temperature environment, sealed slightly with tinfoil, prevents foreign matter from entering nutrient solution, it is small to stand 30
When, solution reaches saturation, and crystal starts to separate out, and with the continuous volatilization of solvent, obtains the transparent crystal of crocus needle-like, is
Curcumin eutectic.
From fig. 1, it can be seen that CU/DHBA is at 7.8 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.5 ° ± 0.2 °, 24 ° ± 0.2 °, 27.9 °
There is the characteristic diffraction peak for being clearly distinguishable from bulk drug (CU and DHBA) at ± 0.2 °, 35.9 ° ± 0.2 °, while in CU and DHBA
Main characteristic peak disappeared in cocrystalization compound, illustrate that CU and DHBA are formd with new crystalline structure by hydrogen bond action
Cocrystalization compound.
It was found from Fig. 2 c, there is CU and DHBA chromatographic peak simultaneously in CU/DHBA HPLC, and appearance time respectively with
CU is consistent with DHBA.On the other hand, in figure 2 c, the ratio between the ratio between CU and DHBA chromatographic peak peak areas amount of same CU, DHBA material
(CU：DHBA) consistent, this explanation CU and DHBA forms cocrystalization compound by intermolecular interaction.
As can be seen from Figure 3, CU fusing point is 186 DEG C, and DHBA fusing point is 206 DEG C, and CU/DHBA fusing point (156 DEG C) is bright
It is aobvious to be different from bulk drug, illustrate CU and DHBA by being self-assembly of cocrystalization compound.
As shown in Figure 4, tested by indoor illumination for three days on end, under the absorbance of curcumin solid powder starts slightly
Drop.In contrast, curcumin-DHB cocrystalization compound absorbance after the experiment of continuous surrounding indoor illumination
It is basically unchanged, illustrates that its photostability is preferable.
Curcumin, curcumin-DHB eutectic solubility in water point when measuring 25 DEG C through HPLC methods
Not Wei 0.38 μ g/mL and 10.6 μ g/mL, the solubility of curcumin cocrystalization compound improves about 28 times.
Embodiment 2
Eutectic is synthesized by solvent room temperature volatility process using curcumin and DHB：
Reactant is by curcumin: DHB=1: 5 mass ratio feeds intake.Accurately claimed with electronic analytical balance
10.00mg curcumin and 50.00mg DHB are taken, is inserted in clear glass bottle.
The dissolving of bulk drug：
Accurately pipette 1mL dichloromethane, 2mL ether and 1mL acetone with liquid-transfering gun to insert in vial, 25 DEG C of temperature strips
Under part, in being stirred 4 hours on magnetic stirring apparatus, stirrer is taken out, between bottle cap and bottle plus one layer of tinfoil increases sealing, twists
Tightly.
Solvent room temperature volatility process：
Vial is placed in room temperature environment, sealed slightly with tinfoil, prevents foreign matter from entering nutrient solution, it is small to stand 30
When, solution reaches saturation, and crystal starts to separate out, and with the continuous volatilization of solvent, obtains the transparent crystal of crocus needle-like, is
Curcumin-DHB pharmaceutical co-crystals.
Embodiment 3
Eutectic is synthesized by solvent room temperature volatility process using curcumin and DHB：
Reactant is by curcumin: DHB=1: 1 mass ratio feeds intake.Accurately claimed with electronic analytical balance
20.00mg curcumin and 20.00mg DHB are taken, is inserted in clear glass bottle.
The dissolving of bulk drug：
Accurately pipette 2mL dichloromethane, 1mL ethanol and 1mL acetone with liquid-transfering gun to insert in vial, 25 DEG C of temperature strips
Under part, in being stirred 4 hours on magnetic stirring apparatus, stirrer is taken out, between bottle cap and bottle plus one layer of tinfoil increases sealing, twists
Tightly.
Solvent room temperature volatility process：
Vial is placed in room temperature environment, sealed slightly with tinfoil, prevents foreign matter from entering nutrient solution, it is small to stand 30
When, solution reaches saturation, and crystal starts to separate out, and with the continuous volatilization of solvent, obtains the transparent crystal of crocus needle-like, is
Curcumin-DHB pharmaceutical co-crystals.
Comparative example 1
Eutectic is synthesized by solvent room temperature volatility process using curcumin and DHB：
Reactant is by curcumin: DHB=1: 10 mass ratio feeds intake.It is accurate with electronic analytical balance
10.00mg curcumin and 100.00mg DHB are weighed, is inserted in clear glass bottle.
The dissolving of bulk drug：
Accurately pipette 2mL dichloromethane, 2mL ether and 1.5mL acetone with liquid-transfering gun to insert in vial, 25 DEG C of temperature
Under the conditions of, in being stirred 4 hours on magnetic stirring apparatus, stirrer is taken out, between bottle cap and bottle plus one layer of tinfoil increases sealing,
Tighten.
Solvent room temperature volatility process：
Vial is placed in room temperature environment, sealed slightly with tinfoil, prevents foreign matter from entering nutrient solution, it is small to stand 30
When, with the continuous volatilization of solvent, brown-red powder being obtained, is tested through PXRD, its diffractive features peak and curcumin are completely the same,
It is curcumin to determine product, fails to obtain cocrystalization compound.
Comparative example 2
Eutectic is synthesized by solvent room temperature volatility process using curcumin and DHB：
Reactant is by curcumin: DHB=1: 1 mass ratio feeds intake.Accurately claimed with electronic analytical balance
20.00mg curcumin and 20.00mg DHB are taken, is inserted in clear glass bottle.
The dissolving of bulk drug：
Accurately pipette 4mL dichloromethane with liquid-transfering gun to insert in vial, under 25 DEG C of temperature conditionss, in magnetic stirring apparatus
Upper stirring 4 hours, takes out stirrer, and between bottle cap and bottle plus one layer of tinfoil increases sealing, tightens.
Solvent room temperature volatility process：
Vial is placed in room temperature environment, sealed slightly with tinfoil, prevents foreign matter from entering nutrient solution, it is small to stand 30
When, with the continuous volatilization of solvent, brown-red powder being obtained, is tested through PXRD, its diffractive features peak and curcumin are completely the same,
It is curcumin to determine product, fails to obtain cocrystalization compound.
Compare, differ only in comparative example 2, described dichloromethane is substituted using single ethanol, ether and acetone,
Experimental result is similar with comparative example 2, can not obtain curcumin-DHB eutectic.
Claims (10)
- A kind of 1. curcumin-DHB eutectic, it is characterised in that：For curcumin and DHB shape Into eutectic.
- 2. curcumin as claimed in claim 1-DHB eutectic, it is characterised in that：It is 1: 0.5 by mass ratio ~1: 5 curcumin and DHB self assembly obtain.
- 3. curcumin as claimed in claim 2-DHB eutectic, it is characterised in that：In dichloromethane, second At least two in the mixed solvent self assembly, volatilization crystallization in alcohol, ether and acetone obtain.
- 4. curcumin-DHB eutectic as described in any one of claims 1 to 3, it is characterised in that：Described Curcumin-DHB eutectic under powder x-ray diffraction, the θ of the angle of diffraction 2 be 7.8 ° ± 0.2 °, 15.8 ° ± There is main characteristic peak at 0.2 °, 17.5 ° ± 0.2 °, 24 ° ± 0.2 °, 27.9 ° ± 0.2 °, 35.9 ° ± 0.2 °.
- 5. curcumin as claimed in claim 4-DHB eutectic, it is characterised in that：Described curcumin -2, 5- dihydroxybenzoic acid cocrystals under powder x-ray diffraction, also the θ of angle of diffraction 2 be 8.8 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.3°±0.2°、21.0°±02°、21.8°±0.2°、29.4°±0.2°、31.5°±0.2°、32.1°±0.2°、36.8° There is characteristic peak at ± 0.2 °, 39.6 ° ± 0.2 °.
- 6. curcumin as claimed in claim 1-DHB eutectic, it is characterised in that：Described curcumin -2, The fusing point of 5- dihydroxybenzoic acid cocrystals is 156 DEG C ± 0.2 DEG C.
- 7. the preparation method of curcumin-DHB eutectic as described in any one of claim 1~6, its feature It is：Step (1)：By curcumin and the DHB self assembly in recrystallisation solvent that mass ratio is 1: 0.5~1: 5；Described recrystallisation solvent is at least two mixed solvent in dichloromethane, ethanol, ether and acetone；The volume ratio of the weight and recrystallisation solvent of curcumin and DHB is 10~25mg/mL；Step (2)：By the solution that step (1) obtains through crystallization, washing, the drying of volatilizing, described curcumin -2,5- dihydroxy is produced Yl benzoic acid eutectic.
- 8. the preparation method of curcumin as claimed in claim 7-DHB eutectic, it is characterised in that：It is described Recrystallisation solvent for dichloromethane, acetone, selectivity include ethanol and ether；Wherein, the volume parts of dichloromethane are 1~4 part；The volume parts of acetone are 1~4 part；The volume parts of ethanol are less than Or equal to 2 parts；The volume parts of ether are less than or equal to 2 parts.
- 9. the preparation method of curcumin as claimed in claim 7-DHB eutectic, it is characterised in that：Step (1) in, the temperature of self assembling process is 20~35 DEG C；Time is 4~12 hours.
- 10. the preparation method of curcumin as claimed in claim 7-DHB eutectic, it is characterised in that：Step (2) in, volatilization recrystallization temperature is room temperature；The speed of volatilization crystallization 24~48 hours；In step (2), in washing process, using described recrystallisation solvent of the temperature less than room temperature as cleaning solvent.
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Cited By (6)
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|---|---|---|---|---|
| CN108840794A (en) * | 2018-06-05 | 2018-11-20 | 山东理工大学 | A kind of novel curcumin pharmaceutical co-crystals and preparation method thereof |
| CN109432055A (en) * | 2018-12-12 | 2019-03-08 | 湖南湘源美东医药科技有限公司 | A kind of composite nanometer particle of polymer overmold curcumin eutectic/piperine and its preparation and the application in sustained release pharmaceutical formulation |
| 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 |
| CN110668932A (en) * | 2019-09-10 | 2020-01-10 | 刘湖 | Co-crystal, preparation method thereof, pharmaceutical composition containing co-crystal and application thereof |
| CN113817012A (en) * | 2021-09-16 | 2021-12-21 | 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 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702092A (en) * | 2012-06-01 | 2012-10-03 | 吉林大学 | Eutectic of two curcumin organic medicaments and preparation method thereof |
| CN103319508A (en) * | 2013-07-09 | 2013-09-25 | 长春市力诚必成新药科技开发有限责任公司 | Cellular structural supramolecular compound with drug molecule serving as ligand and preparation method of cellular structural supramolecular compound |
| WO2012138907A3 (en) * | 2011-04-05 | 2014-05-01 | Translational Genomics Research Institute | Solid forms of curcumin |
| CN104193627A (en) * | 2014-08-18 | 2014-12-10 | 江苏正大清江制药有限公司 | Pharmaceutical co-crystal of ambroxol and 3,4-dihydroxy-benzoic acid and preparation method of pharmaceutical co-crystal |
| 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 |
-
2017
- 2017-11-21 CN CN201711164570.4A patent/CN107827724B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012138907A3 (en) * | 2011-04-05 | 2014-05-01 | Translational Genomics Research Institute | Solid forms of curcumin |
| CN102702092A (en) * | 2012-06-01 | 2012-10-03 | 吉林大学 | Eutectic of two curcumin organic medicaments and preparation method thereof |
| CN103319508A (en) * | 2013-07-09 | 2013-09-25 | 长春市力诚必成新药科技开发有限责任公司 | Cellular structural supramolecular compound with drug molecule serving as ligand and preparation method of cellular structural supramolecular compound |
| CN104193627A (en) * | 2014-08-18 | 2014-12-10 | 江苏正大清江制药有限公司 | Pharmaceutical co-crystal of ambroxol and 3,4-dihydroxy-benzoic acid and preparation method of pharmaceutical co-crystal |
| 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 |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108840794A (en) * | 2018-06-05 | 2018-11-20 | 山东理工大学 | A kind of novel curcumin pharmaceutical co-crystals and preparation method thereof |
| CN108840794B (en) * | 2018-06-05 | 2021-05-14 | 山东理工大学 | Novel curcumin drug cocrystal and preparation method thereof |
| CN109432055A (en) * | 2018-12-12 | 2019-03-08 | 湖南湘源美东医药科技有限公司 | A kind of composite nanometer particle of polymer overmold curcumin eutectic/piperine and its preparation and the application in sustained release pharmaceutical formulation |
| 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 |
| CN110668932A (en) * | 2019-09-10 | 2020-01-10 | 刘湖 | Co-crystal, preparation method thereof, pharmaceutical composition containing co-crystal and application thereof |
| CN110668932B (en) * | 2019-09-10 | 2023-11-03 | 刘湖 | Co-crystal, preparation method, pharmaceutical composition containing co-crystal and application |
| CN113817012A (en) * | 2021-09-16 | 2021-12-21 | 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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