CN104650021A - Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process - Google Patents
Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process Download PDFInfo
- Publication number
- CN104650021A CN104650021A CN201410771442.6A CN201410771442A CN104650021A CN 104650021 A CN104650021 A CN 104650021A CN 201410771442 A CN201410771442 A CN 201410771442A CN 104650021 A CN104650021 A CN 104650021A
- Authority
- CN
- China
- Prior art keywords
- naringenin
- compressed fluid
- solvent precipitation
- fluid anti
- ultrafine particulate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention relates to a method for preparing solid naringenin and particularly relates to a method for preparing naringenin ultrafine particle by using a supercritical compressed fluid anti-solvent precipitation process, so as to produce the naringenin ultrafine particle with an improved dissolution rate. By regulating pressure, temperature, solution concentration, CO2 flow rate and the like, the particle size of the naringenin ultrafine particle can be controlled effectively; the particle size of the prepared naringenin ultrafine particle is in a range of 0.5mu m to 6mu m and the product yield is above 85%. The accumulative release rate of the prepared naringenin ultrafine particle within 240min is increased by 3.2 times in comparison with that of a naringenin raw material.
Description
Technical field
The present invention relates to a kind of method preparing naringenin ultrafine particulate, specifically, the present invention relates to the method using overcritical compressed fluid Anti-solvent Precipitation (PCA) to prepare naringenin ultrafine particulate, for the production of having the ultra-fine grain improving naringenin dissolution rate.
Technical background
Improving one of mode of insoluble drug dissolution rate is by reducing diameter of aspirin particle thus increasing particulate total surface area.Reduce the technology of granularity and have spray-drying process, anti-solvent method, comminution by gas stream, grinding, lyophilize, liquid anti-solvent crystallization and with supercritical fluid precipitation.Compared with other technologies, the supercritical fluid technology developed rapidly has in the last few years attracted great attention, this technology has plurality of advantages as controlled granularity and size-grade distribution, low cost and environmental friendliness characteristic, operational condition is gentle relative not because of thermal stresses or machinery together product degradation, not because of organic solvent and end product produced pollute.
Crystalization in supercritical fluid is prepared microparticle technologies and is comprised: using supercritical fluid quick expansion method (rapid expansion of supercritical Solution, RESS), Supercritical anti-solvent (gas antisolvent recrystallization, GAS), overcritical compressed fluid Anti-solvent Precipitation (precipitation with a compressed anti-solvent method, PCA), supercutical fluid reinforced solution dispersion method (solution enhanced dispersion by supercritical fluids, SEDS) new technology etc. and based on the improvement of above technology obtained.
Naringenin is a class natural flavone compounds, is the aglycon of naringin, is a kind of monomer extracted from rutaceae oil.It is extensively present in orange, lemon, Sucus Vitis viniferae etc.There is stronger anti-inflammatory, scavenging free radicals, anti-oxidant, the sclerosis of anti-artery congee, cytoprotection, and there is antibacterial, anti-inflammatory, anti-hepatitis liver protection effect, antitumor, the multiple pharmacological effect such as anticancer.Research shows, naringenin water solubility is lower, and solubleness is low in the gastrointestinal tract, and dissolution rate is slow, and therefore oral absorption is poor, bioavailability is lower.Making it to reach micron even Nano grade by reducing naringenin particle diameter, improving medicine water solubility, effectively strengthening its adhesion in stomach and intestine, thus be conducive to drug absorption and improve bioavailability.The study hotspot of naringenin be prepare that particle diameter is less, size-grade distribution evenly naringenin medicine, to improve drug availability, reduce toxic side effect.
Summary of the invention
The present invention is to provide the method for the production of the naringenin ultrafine particulate with better dissolution rate.In disclosure method, utilize supercritical CO
2compressed fluid Anti-solvent Precipitation (PCA) prepare naringenin to reduce granularity, thus improve its dissolution rate.Method of the present invention can improve the water solubility of naringenin material, to produce more effective medicine.
In the present invention, the dissolution rate by using PCA process reduction granularity to increase naringenin.Have studied and may affect the granularity of naringenin and the process variable of size-grade distribution, as Tc, crystallization pressure, drug solution concentration, CO
2flow, sample introduction flow velocity etc.Dissolution in vitro experimental study with compare processing with the solubleness of unprocessed naringenin particle.
In the present invention, described method comprises: use acetone solution naringenin to obtain naringenin solution, concentration range is at 1mg/mL ~ 35mg/mL; By CO
2pass into crystallization kettle setting pressure at 8MPa ~ 16MPa, temperature range is at 32 DEG C ~ 60 DEG C; Solution is squeezed into crystallization kettle and is continued to pass into CO with certain flow rate simultaneously by high performance liquid phase pump
2, CO
2flow velocity 0.1L/min ~ 10L/min, solution flow rate is at 0.1mL/min ~ 3.0mL/min; Treat that solution sample introduction terminates, maintain CO
2flow 0.1L/min ~ 10L/min, the release time is 0.5h ~ 10h, to reach the object getting rid of residual solvent; After being progressively depressurized to normal atmosphere in crystallization kettle, opening crystallization kettle and collect naringenin ultrafine particulate.
The inventive method prepares the particle diameter of naringenin ultrafine particulate at 0.5 μm ~ 6 μm, and productive rate reaches more than 80%, processing before diameter of particle be 30 μm ~ 40 μm, process before naringenin be insoluble in water, process after medicine dissolution performance be improved significantly.
Naringenin ultrafine particulate prepared by the present invention is beneficial to absorption of human body, and has rational technology, and easy to operate, yield is higher, and dissolvent residual is extremely low, organic solvent and CO
2recycling capable of circulation.
Accompanying drawing explanation
Fig. 1 is the equipment drawing using the inventive method.
1 CO
2steel cylinder;
2 low temperature thermostat baths;
3 high-pressure pump;
4 container for storing liquids;
5 high performance liquid phase pumps;
6 autoclaves;
7 micrometering valves;
8 solvent recuperation bottles;
9 spinner-type flowmeters.
Fig. 2 is supercritical CO of the present invention
2the naringenin ultrafine particulate that compressed fluid Anti-solvent Precipitation obtains is relative to naringenin bulk drug Dissolution profiles comparison diagram.
Embodiment
Embodiment
Fig. 1 is the equipment drawing implementing the inventive method, and this device mainly comprises carbonic acid gas delivery system, solution delivery system and autoclave, and main implementation process is: the resistance to air loss of check system, opens still top CO
2inlet valve, start the well heater of crystallization kettle.After reaching predetermined temperature inside and outside still, by the CO in steel cylinder
2passed in crystallization kettle from still top by low temperature thermostat bath and high-pressure pump.Until temperature in the kettle and pressure reach stable after, open CO at the bottom of still
2outlet valve, and regulate micrometering valve to predetermined volumetric flow rate.After system stability, the solution prepared is sprayed into crystallization kettle in from still top by nozzle by high pressure pump with certain flow rate, the CO containing solvent
2heat up through throttling valve step-down and enter separating still, in separating still, realize the recovery of solvent, CO
2then discharge through spinner-type flowmeter, stop sample introduction after sample introduction 20ml, continue to pass into CO
2about 30min drains residual solvent, finally closes CO
2inlet valve, opens crystallization kettle and takes out product, obtain naringenin ultrafine particulate after gas reactor is emptying.
Dissolution method: with reference to 2010 editions Chinese Pharmacopoeias, adopts Rotating shaker to measure naringenin ultrafine particulate vitro release.Precision takes quantitative naringenin ultrafine particulate, is placed in and turns basket, with the PBS damping fluid of 500ml for release medium, rotating speed 100r/min, operate at (37 ± 0.5) DEG C in accordance with the law, respectively at scheduled time sampling 5.0ml, and add the blank PBS solution of 5.0ml.Above-mentioned sampling, after 0.22 μm of membrane filtration, measures optical density with ultraviolet spectrophotometer in 286nm place, is converted into the cumulative defaultlogic of different time, the stripping curve figure of m-preparation during drafting.
Compared with naringenin bulk drug, supercritical CO of the present invention
2the dissolution rate of naringenin ultrafine particulate that obtains of compressed fluid Anti-solvent Precipitation and dissolution rate all significantly increase.As shown in Figure 2, the naringenin ultrafine particulate that compressed fluid Anti-solvent Precipitation obtains accumulative release rate in 240min reaches 57%, and naringenin bulk drug only has 18%.The increase of dissolution rate and dissolution rate can owing to critical CO
2the obtained naringenin ultra-fine grain particle size of compressed fluid Anti-solvent Precipitation to be littlely more evenly distributed.Malvern laser particle analyzer is used to measure particle size range at 0.5 μm ~ 6 μm.Extremely low by organic solvent residual in HPLC stratographic analysis sample, conform with the regulations requirement.
Claims (5)
1. use the overcritical particulate preparation system of designed, designed, adopt overcritical compressed fluid Anti-solvent Precipitation to prepare naringenin ultrafine particulate, by changing operating parameters as temperature, pressure, strength of solution and CO
2flow velocity etc. thus control particle morphology, size-grade distribution and efficiency of pcr product.It is characterized in that:
First, by CO
2pass into crystallization kettle and reach supercritical state;
Secondly, use high performance liquid phase pump solution to be squeezed into autoclave to continue to pass into CO with certain flow rate simultaneously
2.
2. the overcritical compressed fluid Anti-solvent Precipitation as described in right 1 prepares the method for naringenin ultrafine particulate, it is characterized in that: pressure range is at 8Mpa ~ 16Mpa, and temperature range is at 32 DEG C ~ 60 DEG C.
3. the overcritical compressed fluid Anti-solvent Precipitation as described in right 1 prepares the method for naringenin ultrafine particulate, it is characterized in that: acetone as solvent, strength of solution scope 1mg/mL ~ 35mg/mL.
4. the overcritical compressed fluid Anti-solvent Precipitation as described in right 1 prepares the method for naringenin ultrafine particulate, it is characterized in that: the flow velocity of constant flow pump at 0.1mL/min ~ 3mL/min, simultaneously CO
2flow velocity 0.1L/min ~ 10L/min.
5. the overcritical compressed fluid Anti-solvent Precipitation according to right 4 prepares the method for naringenin ultrafine particulate, it is characterized in that, when after stopping sample introduction, maintains CO
2flow velocity 0.1L/min ~ 10L/min, the release time is 0.5h ~ 10h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410771442.6A CN104650021A (en) | 2014-12-10 | 2014-12-10 | Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410771442.6A CN104650021A (en) | 2014-12-10 | 2014-12-10 | Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104650021A true CN104650021A (en) | 2015-05-27 |
Family
ID=53241720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410771442.6A Pending CN104650021A (en) | 2014-12-10 | 2014-12-10 | Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104650021A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030683A (en) * | 2015-07-06 | 2015-11-11 | 中国药科大学 | Method for preparing etoposide ultrafine particles by supercutical fluid technology |
| CN105343893A (en) * | 2015-12-11 | 2016-02-24 | 中国药科大学 | Preparation method of acetaminophen-2-hydroxypropyl-beta-cyclodextrin inclusion compound |
| CN106491536A (en) * | 2016-10-20 | 2017-03-15 | 中国药科大学 | One kind utilizes supercritical CO2Prepare the method and system of Gefitinib ultrafine dust |
| CN108159001A (en) * | 2018-01-29 | 2018-06-15 | 安徽工业大学 | A kind of method that overcritical compression fluid precipitation method prepare tripterine nanometer particle |
| CN110200923A (en) * | 2019-06-18 | 2019-09-06 | 中国药科大学 | A method of onocerin ultra-fine grain is prepared using supercritical anti-solvent crystallization technique |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104069069A (en) * | 2014-06-20 | 2014-10-01 | 中国药科大学 | Process for preparing baicalein ultrafine particles by applying supercritical fluid enhancement solution dispersion method |
-
2014
- 2014-12-10 CN CN201410771442.6A patent/CN104650021A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104069069A (en) * | 2014-06-20 | 2014-10-01 | 中国药科大学 | Process for preparing baicalein ultrafine particles by applying supercritical fluid enhancement solution dispersion method |
Non-Patent Citations (2)
| Title |
|---|
| 乐龙等: "超临界流体抗溶剂结晶技术在药物制粒领域中的应用", 《药学进展》 * |
| 薛淼等: "超临界CO2抗溶剂法制备芹菜素微粒的工艺研究", 《中草药》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030683A (en) * | 2015-07-06 | 2015-11-11 | 中国药科大学 | Method for preparing etoposide ultrafine particles by supercutical fluid technology |
| CN105030683B (en) * | 2015-07-06 | 2018-08-10 | 中国药科大学 | A kind of method that supercritical fluid technique prepares Etoposide ultrafine dust |
| CN105343893A (en) * | 2015-12-11 | 2016-02-24 | 中国药科大学 | Preparation method of acetaminophen-2-hydroxypropyl-beta-cyclodextrin inclusion compound |
| CN105343893B (en) * | 2015-12-11 | 2018-07-20 | 中国药科大学 | Paracetamol -2-HP-BETA-CD inclusion compound preparation method |
| CN106491536A (en) * | 2016-10-20 | 2017-03-15 | 中国药科大学 | One kind utilizes supercritical CO2Prepare the method and system of Gefitinib ultrafine dust |
| CN106491536B (en) * | 2016-10-20 | 2019-03-12 | 中国药科大学 | It is a kind of to utilize supercritical CO2Prepare the method and system of Gefitinib ultrafine dust |
| CN108159001A (en) * | 2018-01-29 | 2018-06-15 | 安徽工业大学 | A kind of method that overcritical compression fluid precipitation method prepare tripterine nanometer particle |
| CN108159001B (en) * | 2018-01-29 | 2019-08-09 | 安徽工业大学 | A kind of method that the overcritical compression fluid precipitation method prepare tripterine nanometer particle |
| CN110200923A (en) * | 2019-06-18 | 2019-09-06 | 中国药科大学 | A method of onocerin ultra-fine grain is prepared using supercritical anti-solvent crystallization technique |
| CN110200923B (en) * | 2019-06-18 | 2020-11-20 | 中国药科大学 | Method for preparing formononetin ultrafine particles by using supercritical anti-solvent crystallization technology |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104650021A (en) | Method for preparing naringenin ultrafine particle by using supercritical compressed fluid anti-solvent precipitation process | |
| CN106265596B (en) | Supercritical anti-solvent prepares naringenin/hydroxypropyl-β-cyclodextrin microcapsules method | |
| Tenorio et al. | Controlled submicro particle formation of ampicillin by supercritical antisolvent precipitation | |
| CN104069069B (en) | Process for preparing baicalein ultrafine particles by applying supercritical fluid enhancement solution dispersion method | |
| Montes et al. | Generation of microparticles of ellagic acid by supercritical antisolvent process | |
| CN105534923B (en) | The method for preparing Irbesartan ultra-fine grain using supercritical anti-solvent technology | |
| CN101444709B (en) | Method for obtaining solid particles from water solution by utilizing supercritical carbon dioxide | |
| CN101780113A (en) | Method and device for preparing nanoparticles of effective components of traditional Chinese medicine by supercritical technology | |
| CN100444943C (en) | System for preparing micro particles with hydraulic cavitation reinforcing supercritical auxiliary atomizing and its method | |
| CN103705468B (en) | Utilize the method that ultrasonic assistant supercritical anti-solvent prepares nanocurcumin granule | |
| CN109010289B (en) | Supercritical CO2Method for preparing myricetin ultrafine particles by anti-solvent technology | |
| CN105343893B (en) | Paracetamol -2-HP-BETA-CD inclusion compound preparation method | |
| CN102432008B (en) | Circular carbon dioxide capture device with hydrate method | |
| CN208426691U (en) | A kind of two-way continuous high-pressure fluid ultrasonic extraction instrument | |
| CN206315508U (en) | A kind of extraction element that polyphenol is extracted from Echinacea | |
| CN105030683B (en) | A kind of method that supercritical fluid technique prepares Etoposide ultrafine dust | |
| CN203519395U (en) | Multifunctional micro-nano sample preparation device | |
| CN114605368A (en) | Method for preparing luteolin superfine particles by applying supercritical fluid enhanced solution dispersion technology | |
| CN207605392U (en) | A kind of qinghaosu supercritical extraction unit | |
| CN110200923B (en) | Method for preparing formononetin ultrafine particles by using supercritical anti-solvent crystallization technology | |
| Zhang et al. | Preparation of tetracycline microparticles based on supercritical fluid technique | |
| CN103936816A (en) | Method for purifying tanshinone IIA in salvia miltiorrhiza crude extract through simulated moving bed chromatography | |
| CN206002343U (en) | A kind of slurries sampler | |
| Uzel et al. | A novel method for food particle production using subcritical water extraction: Ganoderma mushroom as a case example | |
| CN106966941A (en) | The method that overcritical compression Anti-solvent Precipitation prepares ezetimibe ultrafine dust |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150527 |