CN107619403A - Quercetin theophylline eutectic and preparation method thereof and the pharmaceutical composition comprising the eutectic - Google Patents
Quercetin theophylline eutectic and preparation method thereof and the pharmaceutical composition comprising the eutectic Download PDFInfo
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- quercetin
- theophylline
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Abstract
Pharmaceutical composition the invention provides a kind of Quercetin theophylline eutectic and preparation method thereof and comprising the eutectic.Described Quercetin theophylline eutectic, it is included in 5.70,6.89,7.16,8.37,8.84,11.41,12.60,13.08,13.73,14.31,17.74,23.10,23.61,24.38,24.75,25.11,25.40,26.76,27.12,27.58,28.03,28.29,28.52,30.64 angle of diffraction represented in X-ray powder diffraction analysis collection of illustrative plates by 2 θ.Preparation method includes：Quercetin and theophylline are added in ethanol or ethanol water, filters, dry after stirring, obtain Quercetin theophylline eutectic.The Quercetin theophylline eutectic that the present invention is prepared can significantly improve solubility of the Quercetin in water, have potential medical applications prospect.
Description
Technical field
The invention belongs to chemical pharmacy field, more particularly to a kind of Quercetin theophylline eutectic and preparation method thereof and comprising
The pharmaceutical composition of the eutectic.
Background technology
Bulk drug and its drug products more than 80% are development and application in solid form.Identical bulk drug can be opened
Different solid-state forms is sent out into, such as：Polymorphic, unformed, hydrate, solvated compoundses, salt and eutectic.Different solid-state forms
With different physicochemical properties, such as：Solubility, stability, dissolution rate, mechanical performance etc., and then influence the biology of medicine
Availability and validity.Select suitable solid-state form developed and produced it is particularly important for pharmaceuticals industry.Crystal work
The physicochemical properties that Cheng Xuewei improves bulk drug provide new approach：Bulk drug is prepared into pharmaceutical co-crystals can improve original
Expect the physicochemical properties of medicine.
Polyphenol compound is present in plant more, and plant polyphenol is the complicated phenols secondary metabolites in plant, main
It is present in the skin of plant, root, leaf, fruit.Plant polyphenol can effectively suppress tumorigenic many stages.Research is compared at present
More has resveratrol, isoflavones, curcumin, Quercetin and Epigallo-catechin gallate (EGCG), but really
Only Quercetin, others for treatment of cancer are mostly used for cancer prevention.
Quercetin, molecular formula C15H10O7, it is widely present in plant, is a kind of natural flavones type organic.Quercitrin
Element has antioxidation.Human body all can take in Quercetin from the common foods such as tea, red wine, vegetables and fruit daily.This
Outer Quercetin also has the effect such as antibacterial, antiallergy and anticancer, has important medical value.However, Quercetin is almost insoluble
In water (37 DEG C, 0.003mg/mL), bioavilability is low, seriously hinders the clinical practice of Quercetin.Therefore, it is necessary to pass through
Suitable technological approaches improves the dissolubility of Quercetin.Have that Quercetin is prepared into its pharmaceutical co-crystals is molten to solve at present
The relevant report of this poor problem of solution property, for example, by Quercetin and caffeine, nicotimine, niacinamide, theobromine, pyridine carboxylic acid,
Proline etc. is prepared into pharmaceutical co-crystals, and wherein Quercetin is molten using methanol with the eutectic that caffeine, nicotimine, theobromine are formed
Agent is prepared, and Quercetin caffeine eutectic can form crystal complex with methanol, not have pharmaceutically acceptable property.Quercetin nicotinoyl
Amine eutectic and Quercetin pyridine carboxylic acid eutectic are obtained using polishing, but this method can not be applied to pharmaceuticals industry.And Quercetin
The preparation of proline eutectic needs to use a large amount of ethyl acetate, and ethyl acetate is volatile as solvent, not environmentally friendly enough, and formed
Amount ratio (the Quercetin of raw material molecular substance in eutectic:Proline) it is 1:2, quercetin content is slightly lower.
In addition, in the Quercetin eutectic preparation method reported, polishing and suspension method are used mostly.Polishing can not
Apply in pharmaceuticals industry, suspension method is mostly solvent using methanol, has potential safety hazard.
The content of the invention
Goal of the invention：To overcome the problems of the prior art, an object of the present invention is to provide a kind of Quercetin theophylline
Eutectic, can overcome in existing Quercetin poorly water-soluble, existing Quercetin eutectic active constituent content is low, security is poor, system
The problems such as Preparation Method complexity.It is a further object to provide the preparation method of the Quercetin theophylline eutectic.The present invention
A further object be to provide the pharmaceutical composition for including the Quercetin theophylline eutectic.
Technical scheme：Quercetin theophylline eutectic of the present invention, it is included in X-ray powder diffraction analysis collection of illustrative plates (example
Such as, radiation source is CuK α) in by 2 θ represent 5.70,6.89,7.16,8.37,8.84,11.41,12.60,13.08,13.73,
14.31、17.74、23.10、23.61、24.38、24.75、25.11、25.40、26.76、27.12、27.58、28.03、
28.29th, 28.52,30.64 angle of diffraction.
Infrared absorption spectroscopy shows, the Quercetin theophylline eutectic is 3379,3223,3142,3089,3001,2903,
2709、2622、1701、1640、1562、1507、1443、1395、1370、1344、1309、1261、1238、1201、1164、
1105th, 1088,1064,997,958,929,874,819,762,745,706,687,640,609,502,457 and 419cm-1Place
With characteristic absorption peak.
13C solid-state nuclear magnetic resonances spectrum (for example, being calibrated with tetramethylsilane, 0ppm) display, the Quercetin theophylline eutectic exist
174.5、162.2、160.9、158.4、154.8、151.3、149.6、147.6、145.0、144.0、143.0、135.7、
122.2、120.5、119.3、118.5、116.9、115.0、106.7、104.4、102.9、98.1、96.3、32.6、30.3、
There is characteristic peak at 29.2ppm.The structure cell of the Quercetin theophylline eutectic belongs to monoclinic system, structure cell axial length Shaft angle α=90.00 °, β=105.0300 (3) °, γ
=90.00 °.
In described Quercetin theophylline eutectic, quercetin molecule, the mol ratio of theophylline molecule are 1:1.
Present invention also offers the preparation method of the Quercetin theophylline eutectic, including：Quercetin and theophylline are added to
In ethanol or ethanol water, filtered after 20~60 DEG C of 6~24h of stirring, after filtering gained powder is dried, obtain Quercetin theophylline
Eutectic.
The starting molar ratio of Quercetin and theophylline is 1:1~1:4.
Above-mentioned eutectic can be obtained using ethanol and ethanol water, in ethanol water, the volume of ethanol and water
Than for 1:1~3:1.
Using vacuum drying when drying.Dry temperature is 20~40 DEG C.
Present invention also offers a kind of pharmaceutical composition, includes described Quercetin theophylline eutectic.
Beneficial effect：
The present invention is guest molecule using theophylline, the use of ethanol or ethanol water is that solvent prepares Mongolian oak by suspension method
Skin element theophylline eutectic, participated in without poisonous and volatile solvent, and experimental method and equipment are simple.
The Quercetin theophylline eutectic that the present invention is prepared can significantly improve solubility of the Quercetin in water, have potential
Medical applications prospect.
The pharmaceutical co-crystals preparation method that the present invention uses is suspension method, and equipment is simple, available for pharmaceuticals industry.And nothing has
Poison and volatile solvent participate in, to free of air pollution.
Brief description of the drawings
Fig. 1 is obtained the Powder XRD pattern of Quercetin theophylline eutectic by embodiment 1；
Fig. 2 is obtained the FTIR spectrograms of Quercetin theophylline eutectic by embodiment 1；
Fig. 3 obtains Quercetin theophylline eutectic by embodiment 113C solid state nmr spectrograms；
Fig. 4 obtains dissolubility picture of the Quercetin theophylline eutectic in water by embodiment 1.
Embodiment
With reference to specific embodiment, the present invention is furture elucidated, it should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention, after the present invention has been read, various equivalences of the those skilled in the art to the present invention
The modification of form falls within the application appended claims limited range.
Embodiment 1
The preparation method of Quercetin theophylline eutectic is as follows：1mmol Quercetins and 1mmol theophylline are weighed in small reagent bottle,
Add 8mL ethanol water (ethanol:Water (volume ratio)=2:1) 6h, is stirred at room temperature.Gained powder placement vacuum is done after filtering
40 DEG C of dryings in dry case, obtain Quercetin theophylline eutectic 376mg.Yield 78.0%.
X-ray diffraction analysis, FTIR analyses and solid-state nuclear magnetic resonance point are carried out to the Quercetin theophylline eutectic being prepared
Analysis.
X-ray diffraction analysis use Bruker D8ADVANCE x-ray powder diffraction instruments, condition determination：Cu K α radiations,
Voltage 45kV, electric current 40mA, 0.015 ° of 5-40 ° of scanning step of scanning range often walk stand-by period 19.2s.FTIR infrared absorption light
Spectrum is obtained by the analysis test of KBr pressed disc methods.13C solid-state nuclear magnetic resonances use Bruker AVANCE III-500 solid-state nuclear magnetic resonances
Instrument, test condition：Magnetic field intensity 11.7T, 4mm double resonance are popped one's head in, Magic angle spinning frequency 8kHz, time of contact 2.0ms.
Determine the solubility of Quercetin theophylline eutectic.Assay method is：Take each 10mg points of Quercetin theophylline eutectic, Quercetin
Not in 10mL plastic centrifuge tubes, 5mL ultra-pure waters are added.The centrifugation seal of tube is positioned in shaking table, 37 DEG C of shaking table design temperature,
Shake 24h.Afterwards, suspension is determined into solubility after 0.22 μm of membrane filtration through high performance liquid chromatography.
X-ray diffraction analysis result referring to Fig. 1, Quercetin theophylline eutectic have by 2 θ represent 5.70,6.89,7.16,
8.37、8.84、11.41、12.60、13.08、13.73、14.31、17.74、23.10、23.61、24.38、24.75、25.11、
25.40th, 26.76,27.12,27.58,28.03,28.29,28.52,30.64 angle of diffraction.Quercetin theophylline eutectic mainly by
Mol ratio 1:1 quercetin molecule, theophylline molecular composition, and the structure cell of eutectic belongs to monoclinic system, structure cell axial length Shaft angle α=90.00 °, β=105.0300 (3) °, γ
=90.00 °.
Infrared absorption spectroscopy (Fig. 2) shows, Quercetin theophylline eutectic is 3379,3223,3142,3089,3001,2903,
2709、2622、1701、1640、1562、1507、1443、1395、1370、1344、1309、1261、1238、1201、1164、
1105th, 1088,1064,997,958,929,874,819,762,745,706,687,640,609,502,457 and 419cm-1Place
There is absworption peak.
13C solid-state nuclear magnetic resonances spectrum (for example, being calibrated with tetramethylsilane, 0ppm) display, Quercetin theophylline eutectic exist
174.5、162.2、160.9、158.4、154.8、151.3、149.6、147.6、145.0、144.0、143.0、135.7、
122.2、120.5、119.3、118.5、116.9、115.0、106.7、104.4、102.9、98.1、96.3、32.6、30.3、
There is characteristic peak at 29.2ppm.
Solubility results are shown in Fig. 4, lead to hypereutectic formation, and solubility of the Quercetin in water is brought up to from 0.003mg/mL
0.011mg/mL, improves 2.7 times.
Embodiment 2
The preparation method of Quercetin theophylline eutectic is as follows：1mmol Quercetins and 1mmol theophylline are weighed in small reagent bottle,
Add 5mL ethanol, (25 DEG C) stirring 6h of room temperature.Gained powder is placed into 40 DEG C of dryings in vacuum drying chamber after filtering, obtains Mongolian oak
Skin element theophylline eutectic 361mg.Yield 74.9%.
X ray diffracting spectrum, infrared absorption spectroscopy spectrogram,13C solid-state nuclear magnetic resonances spectrogram is close with Fig. 1,2,3 respectively, table
Above-mentioned eutectic can be prepared by showing.
Embodiment 3
The preparation method of Quercetin theophylline eutectic is as follows：1mmol Quercetins and 2mmol theophylline are weighed in small reagent bottle,
5mL ethanol is added, 6h is stirred at room temperature.Gained powder is placed into 40 DEG C of dryings in vacuum drying chamber after filtering, obtains Quercetin tea
Alkali eutectic 396mg.Yield 59.8%.
X ray diffracting spectrum, infrared absorption spectroscopy spectrogram,13C solid-state nuclear magnetic resonances spectrogram is consistent with Fig. 1,2,3 respectively, table
Above-mentioned eutectic can be prepared by showing.
Embodiment 4
The preparation method of Quercetin theophylline eutectic is as follows：1mmol Quercetins and 1mmol theophylline are weighed in small reagent bottle,
Add 5mL ethanol, 40 DEG C of stirring 24h.Gained powder is placed into 20 DEG C of dryings in vacuum drying chamber after filtering, obtains Quercetin tea
Alkali eutectic 339mg.Yield 70.3%.
X ray diffracting spectrum, infrared absorption spectroscopy spectrogram,13C solid-state nuclear magnetic resonances spectrogram is consistent with Fig. 1,2,3 respectively, table
Above-mentioned eutectic can be prepared by showing.
Embodiment 5
The preparation method of Quercetin theophylline eutectic is as follows：1mmol Quercetins and 1mmol theophylline are weighed in small reagent bottle,
Add 8mL ethanol water (ethanol:Water (volume ratio)=2:1), 60 DEG C of stirring 12h.Gained powder is placed into vacuum after filtering
30 DEG C of dryings in drying box, obtain Quercetin theophylline eutectic 352mg.Yield 73.0%.
X ray diffracting spectrum, infrared absorption spectroscopy spectrogram,13C solid-state nuclear magnetic resonances spectrogram is consistent with Fig. 1,2,3 respectively, table
Above-mentioned eutectic can be prepared by showing.
Embodiment 6
The preparation method of Quercetin theophylline eutectic is as follows：1mmol Quercetins and 4mmol theophylline are weighed in small reagent bottle,
5mL ethanol is added, 6h is stirred at room temperature.Gained powder is placed into 40 DEG C of dryings in vacuum drying chamber after filtering, obtains Quercetin tea
Alkali eutectic 644mg.Yield 63.0%.
X ray diffracting spectrum, infrared absorption spectroscopy spectrogram,13C solid-state nuclear magnetic resonances spectrogram is consistent with Fig. 1,2,3 respectively, table
Above-mentioned eutectic can be prepared by showing.
Claims (9)
1. a kind of Quercetin theophylline eutectic, it is characterised in that it is included in what is represented in X-ray powder diffraction analysis collection of illustrative plates by 2 θ
5.70、6.89、7.16、8.37、8.84、11.41、12.60、13.08、13.73、14.31、17.74、23.10、23.61、
24.38th, 24.75,25.11,25.40,26.76,27.12,27.58,28.03,28.29,28.52,30.64 angle of diffraction.
2. Quercetin theophylline eutectic according to claim 1, it is characterised in that quercetin molecule, mole of theophylline molecule
Than for 1:1.
3. Quercetin theophylline eutectic according to claim 1, it is characterised in that the structure cell category of the Quercetin theophylline eutectic
In monoclinic system, structure cell axial length Shaft angle α=
90.00 °, β=105.0300 (3) °, γ=90.00 °.
4. Quercetin theophylline eutectic according to claim 1, it is characterised in that infrared absorption spectroscopy shows, the quercitrin
Plain theophylline eutectic is 3379,3223,3142,3089,3001,2903,2709,2622,1701,1640,1562,1507,1443,
1395、1370、1344、1309、1261、1238、1201、1164、1105、1088、1064、997、958、929、874、819、
762nd, 745,706,687,640,609,502,457 and 419cm-1Place has characteristic absorption peak.
5. Quercetin theophylline eutectic according to claim 1, it is characterised in that13The spectrum display of C solid-state nuclear magnetic resonances, it is described
Quercetin theophylline eutectic is 174.5,162.2,160.9,158.4,154.8,151.3,149.6,147.6,145.0,144.0,
143.0、135.7、122.2、120.5、119.3、118.5、116.9、115.0、106.7、104.4、102.9、98.1、96.3、
32.6th, 30.3, there is characteristic peak at 29.2ppm.
6. the preparation method of the Quercetin theophylline eutectic according to any one of Claims 1 to 5, it is characterised in that including：Will
Quercetin and theophylline are added in ethanol or ethanol water, are filtered after 20~40 DEG C of 6~24h of stirring, by filtering gained powder
After drying, Quercetin theophylline eutectic is obtained.
7. the preparation method of Quercetin theophylline eutectic according to claim 6, it is characterised in that of Quercetin and theophylline
Beginning molar ratio is 1:1~1:4.
8. the preparation method of Quercetin theophylline eutectic according to claim 6, it is characterised in that dry temperature be 20~
40℃。
9. a kind of pharmaceutical composition, it is characterised in that include the Quercetin theophylline eutectic described in any one of claim 1~6.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008153945A2 (en) * | 2007-06-06 | 2008-12-18 | University Of South Florida | Nutraceutical co-crystal compositions |
| CN103980276A (en) * | 2014-05-26 | 2014-08-13 | 中国药科大学 | Quercetin caffeine eutectic |
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2017
- 2017-09-26 CN CN201710880838.8A patent/CN107619403A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008153945A2 (en) * | 2007-06-06 | 2008-12-18 | University Of South Florida | Nutraceutical co-crystal compositions |
| CN103980276A (en) * | 2014-05-26 | 2014-08-13 | 中国药科大学 | Quercetin caffeine eutectic |
Non-Patent Citations (2)
| Title |
|---|
| 周新波等: "中药难溶性有效成分共晶的研究进展", 《中草药》 * |
| 黄雨婷: "药物共晶筛选技术的研究进展", 《国际药学研究杂志》 * |
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