CN106432389B - A kind of method that estradiol ultrafine dust is prepared using supercritical anti-solvent technology - Google Patents

A kind of method that estradiol ultrafine dust is prepared using supercritical anti-solvent technology Download PDF

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CN106432389B
CN106432389B CN201610817454.7A CN201610817454A CN106432389B CN 106432389 B CN106432389 B CN 106432389B CN 201610817454 A CN201610817454 A CN 201610817454A CN 106432389 B CN106432389 B CN 106432389B
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estradiol
pressure
crystallization kettle
passed
temperature
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CN106432389A (en
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王志祥
刘尚德
缪虹刚
王为彦
宋雅琴
高赵华
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of method that estradiol ultrafine dust is prepared using supercritical anti-solvent technology, comprise the following steps：Step S1, estradiol is dissolved in organic solvent, obtains estradiol solution；Step S2, by CO2It is passed through in crystallization kettle, adjusts the temperature and pressure in crystallization kettle；Step S3, continue to be passed through CO with certain flow rate2, maintain the temperature and pressure in crystallization kettle constant, while estradiol solution prepared by step S1 is passed through in crystallization kettle；Step S4, after estradiol solution is passed through, it is continually fed into CO2, maintain the temperature and pressure in crystallization kettle constant, release after a period of time；After pressure is down to atmospheric pressure in crystallization kettle, opens crystallization kettle and collect estradiol ultrafine dust；Wherein, sequencing is not present in step S1 and step S2；The organic solvent is the mixed solvent of acetone and ethanol.The inventive method can prepare the tiny estradiol of particle diameter, improve its solubility in water, and then improve its bioavilability.

Description

A kind of method that estradiol ultrafine dust is prepared using supercritical anti-solvent technology
Technical field
The present invention relates to the preparation of estradiol ultrafine dust, and in particular to one kind prepares female using supercritical anti-solvent technology The method of glycol ultrafine dust.
Background technology
Potentiality are huge in terms of ultrafine dust is prepared for supercritical anti-solvent (Supercritical Anti-solvent, SAS) Greatly, its operating condition is gentle, and the miniaturization to biological products, antibiotic medicine and pharmaceutical carrier is especially suitable.With being spray-dried, Traditional method of granulating such as air-flow crushing, grinding, freeze-drying is compared, and its major advantage is the particulate organic solvent being prepared It is remaining less, reaction condition it is gentle, can prevent thermal sensitivity medicine from being thermally decomposed, the particle diameter of synthesis particle and distribution, morphology controllable etc..
Supercritical CO2Anti-dissolving agent process is that solute is dissolved into suitable solvent into (being usually organic solvent), forms one Determine the solution of concentration, then make solution and supercritical CO2Contact, because solute is in supercritical CO2In solubility be much smaller than molten Solubility in agent, both quick phase counterdiffusion, solvent volume expansion, density decline after contact, dissolving energy of the solvent to solute Power reduces, and moment forms higher degree of supersaturation and separates out lolute crystallization, forms purity height, the uniform superfine of particle diameter distribution Grain.
According to the difference of mode of operation, supercritical anti-solvent technology can be divided into gas antisolvent (GasAnti- Solvent, abbreviation GAS), Aerosol Solvent Extraction method (Aerosol Solvent Extraction System, abbreviation ASES) Or compression fluid Anti-solvent Precipitation (Precipitation with a Compressed Fluid Anti-solvent, Abbreviation PCA), supercritical fluid enhancing solution dispersion method (Solution Enhanced Dispersion by Supercritical Fluids, abbreviation SEDS) etc..Wherein, the major advantage of PCA methods is that liquid forms droplet by nozzle It is distributed in supercritical fluid, exacerbates the diffusion mass transfer between supercritical fluid and solution, solute is with smaller particle form Precipitation, from prepared by drug microparticles particle diameter it is smaller.
Estradiol is a kind of steroid hormone by ovarian secretion, is the main estrogen secreted in Pre-menopausal Women ovary One of, and the female hormone that endogenous is most strong.It is mainly used in controversies in hormone replacement in the elderly (ERT), prevention and treatment climacteric is comprehensive Simulator sickness, alzheimer's disease, and have preferably to functional uterine bleeding, advanced breast cancer, prostate cancer, acne and contraception etc. The effect of.Estradiol solubility in water is very low, causes oral administration biaavailability very low, and only 10% or so.If it can reduce The particle diameter of estradiol, then it is expected to improve its solubility in water, and then improves its bioavilability.
The content of the invention
It is an object of the invention to provide a kind of method that estradiol ultrafine dust is prepared using supercritical anti-solvent technology, with The tiny estradiol of particle diameter is prepared, improves its solubility in water, and then improve its bioavilability.
Above-mentioned purpose is achieved by the following technical solution：
A kind of method that estradiol ultrafine dust is prepared using Supercritical anti-solvent, comprises the following steps：
Step S1, estradiol is dissolved in organic solvent, obtains estradiol solution；
Step S2, by CO2It is passed through in crystallization kettle, adjusts the temperature and pressure in crystallization kettle；
Step S3, continue to be passed through CO with certain flow rate2, maintain the temperature and pressure in crystallization kettle constant, while by step Estradiol solution prepared by S1 is passed through in crystallization kettle；
Step S4, after estradiol solution is passed through, it is continually fed into CO2, maintain the temperature and pressure in crystallization kettle constant, Release after a period of time；After pressure is down to atmospheric pressure in crystallization kettle, opens crystallization kettle and collect estradiol ultrafine dust；
Wherein, sequencing is not present in step S1 and step S2.
Preferably, the organic solvent is the mixed solvent of acetone and ethanol, and the two is according to volume ratio 1:1 mixing.
Preferably, the mass concentration of estradiol solution is 6-10mg/mL.
Preferably, step S2 adjusts temperature in crystallization kettle to 35-50 DEG C, pressure to 8-18MPa.
Preferably, step S3 maintains CO2The flow velocity that is passed through be 2-4L/min.
Preferably, the volume flow that estradiol solution is passed through crystallization kettle in step S3 is 0.6-1.4mL/min.
Preferably, it is 0.5-2h for a period of time described in step S4.
Preferably, the mass concentration of estradiol solution is 8mg/mL；CO2The flow velocity for being passed through crystallization kettle is 3L/min；Crystallization Temperature in the kettle is 40 DEG C, pressure 14MPa；The volume flow of estradiol solution is 1.0mL/min；Release after 40 minutes.
Preferably, the mass concentration of estradiol solution is 6mg/mL；CO2The flow velocity for being passed through crystallization kettle is 3L/min；Crystallization Temperature in the kettle is 55 DEG C, pressure 8MPa；The volume flow of estradiol solution is 1.0mL/min；Release after 40 minutes.
Preferably, the organic solvent is the mixed solvent of ethanol and acetone, and the two is according to volume ratio 1:2 mixing；Female two The mass concentration of alcoholic solution is 6mg/mL；CO2The flow velocity for being passed through crystallization kettle is 3L/min；It is 55 DEG C to crystallize temperature in the kettle, pressure For 8MPa；The volume flow of estradiol solution is 1.0mL/min；Release after 40 minutes.
Beneficial effects of the present invention：
Method provided by the invention can prepare the tiny estradiol of particle diameter, improve its solubility in water, and then Improve its bioavilability；The parameters optimization method of the inventive method is reasonable, and the estradiol grain diameter prepared is tiny, And the rate of recovery is high.The inventive method compared with prior art, has prominent substantive distinguishing features and significant progress.
Brief description of the drawings
Fig. 1：Supercritical anti-solvent device structure installation drawing；
Fig. 2：Crystallization kettle pressure is to estradiol grain diameter and the influence graph of relation of the rate of recovery；
Fig. 3：The mass concentration of estradiol solution is to estradiol grain diameter and the influence graph of relation of the rate of recovery；
Fig. 4：The volume flow of estradiol solution is to estradiol grain diameter and the influence graph of relation of the rate of recovery；
Fig. 5：The dissolution rate contrast curve of estradiol bulk drug and estradiol ultrafine dust；
In figure：1、CO2Steel cylinder；2nd, constant temperature circulator；3rd, high-pressure pump；4th, fluid reservoir；5th, efficient liquid phase pump；6th, crystallization kettle； 7th, metallic filter；8th, solvent recycler；9th, spinner flowmeter.
Embodiment
Technical scheme is specifically introduced with reference to embodiment.
Embodiment 1：Single_factor method determines the preferred span of each key parameter
Instrument and material
Experiment material is shown in Table 1, and laboratory apparatus is shown in Table 2.
The experiment material of table 1
Title material Specification Manufacturer
Estradiol >=99% Wuhan Bel's card biological medicine Co., Ltd
CO2 >=99% Nanjing is the same as gas gas companies
Ethanol Analyze pure Nanjing Chemistry Reagent Co., Ltd.
Acetone Analyze pure Nanjing Chemistry Reagent Co., Ltd.
Dichloromethane Analyze pure Nanjing Chemistry Reagent Co., Ltd.
Methanol Analyze pure Nanjing Chemistry Reagent Co., Ltd.
Dimethyl sulfoxide (DMSO) Analyze pure Nanjing Chemistry Reagent Co., Ltd.
The laboratory apparatus of table 2
Device name Model Manufacturer
Overcritical particulate preparation system Helix Applied Separations companies of the U.S.
Intelligent dissolution experiment instrument ZRS-8L Tianjin Tianda Tianfa Science and Technology Co. Ltd.
Laser particle size analyzer MS2000 Malvern companies of Britain
Ultraviolet-uisible spectrophotometer UV-1800 Japanese Shimadzu Corporation
Electronic balance JY1002 Shanghai Precision Scientific Apparatus Co., Ltd
Low temperature thermostat bath L-1500 Nanjing Xin Chen bio tech ltd
High pressure pump L-1500 Applied Separations companies of the U.S.
Numerical control ultrasonic cleaner KH-250DB Kunshan He Chuan ultrasonic instruments Co., Ltd
Gas bath isothermal vibration instrument ZD-85 Changzhou Guohua Electric Appliance Co., Ltd.
Supercritical anti-solvent equipment and operating process
Supercritical anti-solvent equipment is shown in Fig. 1.Operating process is as follows：
(1) in the state of ensureing that all valves of instrument are turned off, Flowmeter Inlet valves are opened；
(2) filter is installed, each valve on crystallization kettle is twisted, connects the socket of all kinds of detectors, then opens each heating Switch；
(3) some sample solution cleaning Solvent pump are led to；
(4) Top Inlet valves are opened, CO is poured into kettle2, system keeps stable after a period of time, it is ensured that temperature in kettle After reaching preset temperature, then force (forcing) pump is opened to CO2Preset pressure is forced into, then outwards winding Vessel Button Outlet, Flow is adjusted, is kept for a period of time make system stable, while whole system can be cleaned；About 30min is completed；At this moment it is believed that State in kettle is stable above-critical state；
(5) Solvent Pump are opened and sample solution is squeezed into kettle；
(6) Solvent Pump are closed, maintain CO2Flow constant a period of time, make kettle endoparticle dry；
(7) CO is closed2Cylinder valve and force (forcing) pump, decline in kettle pressure, about with steel cylinder pressure it is similar when, close Top Inlet, continue to be vented, after the completion of close system；
(8) obtained sample is collected；
(9) whole system is thoroughly cleaned.
Experiment of single factor：The influence of solvent species
45 DEG C, pressure 12MPa, volume flow 1mL/min of crystallization temperature, under the conditions of mass concentration 8mg/mL, set different Solvent (methanol, ethanol, acetone, the mixed solution of dichloromethane different proportion) be compared research.Wherein due to methanol and Dichloromethane is smaller to the solubility of estradiol, therefore considers to add a small amount of DMSO as cosolvent.As a result it is as shown in table 3.
Shown from result, when methanol is used as solvent, its particle diameter is smaller, but after a small amount of DMSO of addition, drains solvent Process becomes very difficult, easily causes the reunion of product and moist phenomenon；During using the larger miscible agent of proportion of ethanol, its grain Footpath, the rate of recovery and pattern are all preferable, but proportion of ethanol is unsuitable excessive, the dissolving of estradiol otherwise can be caused difficult, and drain The difficulty of dissolving agent process.Therefore pass through and consider, it is 1 to select ethanol and acetone volume ratio:1 miscible fluid is as solvent.
Influence of the solvent species of table 3 to estradiol diameter of particle, the rate of recovery and pattern
Experiment of single factor：The influence of crystallization pressure
Under the conditions of 45 DEG C, volume flow 1mL/min, mass concentration 8mg/mL of crystallization temperature, different crystallization pressures is set (8,10,12,14,16,18MPa) be compared research.With the increase of system pressure, particle diameter first reduces and increased afterwards, the rate of recovery First increases and then decreases.As a result it is as shown in Figure 2.
This phenomenon is probably that the minor variations of pressure will cause CO because near critical condition2The huge of property changes Become, pressure is bigger, and density is bigger, SC-CO2Mass transfer between organic solvent is rapider, and solute moment is supersaturated and analyses Go out, because process is rapid, so nucleation is small；Simultaneously because solute is separated out rapidly, so the rate of recovery is higher.But when pressure continues When being increased to certain numerical value, change of the diffusion coefficient to pressure is no longer sensitive, and mass transfer effect weakens, and causes particle diameter to increase, and reclaims Rate reduces.
Accordingly, it is determined that the preferred scope of crystallization pressure is 10-14MPa.
Experiment of single factor：The influence of crystallization temperature
Under the conditions of crystallization pressure 12MPa, volume flow 1mL/min, mass concentration 8mg/mL, different crystallization temperatures are set (35,40,45,50,55 DEG C) are compared research.As a result show, when temperature is 35,40,45,50 DEG C, average grain diameter difference For 17.25,14.03,9.07,15.92 μm；The rate of recovery is 44.2%, 43.5%, 72.3%, 68.5%.And when temperature is 55 DEG C When, by repetition test, in moist, viscous pasty state, dry solia particle can not be made in obtained product.
Raised with temperature, diameter of particle reduces, rate of recovery increase, it may be possible to due to being raised with temperature, the viscosity of solution Reduce, solvent and supercritical CO2Between mass transfer enhancing and cause.And when more than 50 DEG C, may be higher due to temperature, to production The coherent condition of thing impacts, therefore obtained product is in aggregating state.
Accordingly, it is determined that the preferred scope of crystallization temperature is 40-50 DEG C.
Experiment of single factor：The influence of estradiol concentration of polymer solution
Crystallization pressure 12MPa, 45 DEG C of crystallization temperature, under the conditions of volume flow 1mL/min, different estradiol sample introduction matter are set Amount concentration (6,7,8,9,10,11mg/mL) be compared research.When estradiol mass concentration increases, the increase of its product cut size, The rate of recovery reduces.When the mass concentration of estradiol it is excessive (>When 12mg/ml), its dissolving in mixed solution can become difficult. As a result it is as shown in Figure 3.
Reason is probably the solution viscosity increase as concentration increases, and solution atomization effect is bad so that SC-CO2With it is organic Solution contact surface product diminishes, and mass transfer effect weakens, and causes particle diameter to become big, the rate of recovery reduces.But when mass concentration is too low, during sample introduction Between it is longer, obtain the less efficient of product.
Accordingly, it is determined that the preferred scope of estradiol concentration of polymer solution is 7-9mg/ml.
Experiment of single factor：The influence of estradiol liquor capacity flow
Crystallization pressure 12MPa, 45 DEG C of crystallization temperature, under the conditions of mass concentration 8mg/mL, different volume flows is set (0.6,0.8,1.0,1.2,1.4mL/min) be compared research.With the increase of volume flow, product cut size first reduces and increased afterwards Greatly, rate of recovery first increases and then decreases.As a result it is as shown in Figure 4.
When estradiol volume flow is too low, crystallization solution does not reach preferably atomization effect by nozzle into crystallization kettle Fruit, initial liquid drop can be made to become big, while nozzle has the phenomenon of blocking in course of injection, and sample injection time is longer, produces work The efficiency of skill is low；And when volume flow is excessive so that SC-CO2Reduce with organic solution time of contact, contact area reduces, and passes Matter decreased effectiveness, causes degree of supersaturation to reduce, and the particle diameter finally given is larger, and the rate of recovery is relatively low.
Accordingly, it is determined that the preferred scope of estradiol solution flow rate is 0.8-1.2mL/min.
Embodiment 2：Orthogonal experiment optimizes optimized parameter in the preferred scope of each key parameter
Orthogonal and result
Using particle diameter as main evaluation index, select to influence obvious 4 factors, liquor capacity to estradiol diameter of particle Flow (A), crystallization pressure (B), crystallization temperature (C) and estradiol mass concentration (D) are investigated, and use L9 (34) orthogonal experiment Design is tested, and its factor level is determined by the experiment of single factor of embodiment 1, is shown in Table 4.Other process conditions are CO2 The volume ratio 1 of exhaust volumetric flow 3L/min, acetone and ethanol:1.Experimental design and it the results are shown in Table 5.
The orthogonal experiment factor of table 4 and water-glass
The orthogonal of table 5 and result
Tested number A B C D Particle diameter (μm)
1 0.8 10 40 7 14.66
2 0.8 12 45 8 10.42
3 0.8 14 50 9 12.57
4 1.0 10 45 9 10.23
5 1.0 12 50 7 8.94
6 1.0 14 40 8 7.36
7 1.2 10 50 8 8.59
8 1.2 12 40 9 13.87
9 1.2 14 45 7 13.80
K1 12.550 11.160 11.963 12.467
K2 8.843 11.077 11.483 8.790
K3 12.087 11.243 10.033 12.223
R 3.707 0.166 1.930 3.677
Orthogonal experiment results are analyzed
From variance analysis and analysis directly perceived, influence of each factor to estradiol particulate average grain diameter is A from big to small> D>C>B, i.e. volume flow>Mass concentration>Crystallization temperature>Crystallization pressure；Selection process is combined as A2B3C1D2, ie in solution volume Flow 1.0mL/min, crystallization pressure 14MPa, 40 DEG C of crystallization temperature, estradiol mass concentration 8mg/mL.
Therefore deduce that optimized parameter is as follows：
(solvent is acetone to estradiol solution and ethanol volume ratio is 1:1) mass concentration is 8mg/mL；Estradiol solution Volume flow be 1.0mL/min；CO2The flow velocity for being passed through crystallization kettle is 3L/min；Crystallization temperature is 40 DEG C, and crystallization pressure is 14MPa。
The solubility test for the estradiol ultrafine dust that optimized parameter condition obtains
In 3 100mL conical flask with cover, a certain amount of distilled water, 2% hydrochloric acid solution, pH=7.4 phosphoric acid are separately added into Cushioning liquid, then excessive estradiol bulk drug, preferably particulate are separately added into, it is placed in air concussion shaking table, is kept for 37 DEG C and shaken 72h is shaken, is sampled, insulation filtering, the estradiol amount of dissolving is determined, calculates its equilbrium solubility in each medium.It the results are shown in Table 6。
As shown in Table 6, equilbrium solubility of the before processing estradiol in water is extremely low, only 1.440 μ g/mL, and optimal work The ultrafine dust equilbrium solubility of skill can reach 4.378 μ g/mL, improve three times or so.In 0.2% hydrochloric acid solution and pH= Its solubility has also obtained the raising of several times in 7.4 PBS.
The estradiol solubility of table 6 (μ g/mL)
The Their Dissolution Test in vitro for the estradiol ultrafine dust that optimized parameter condition obtains
Reference《Chinese Pharmacopoeia》2015 editions two methods of annex XC second, are surveyed under temperature (37 ± 0.5), rotating speed 100r/min Determine the In Vitro Dissolution curve of estradiol.Precision weighs appropriate amount of sample, is placed in and turns to be tested in basket, respectively 5,10,20,30, 40th, 50,60,90,120,150,180,210,240min respectively samples 5.0mL, while adds 5.0mL and be situated between with the dissolution of equitemperature Matter.Sample is after 0.22 μm of membrane filtration, and with phosphate buffered saline solution (pH7.4) for blank control, its suction is determined at 276nm Luminosity, cumulative release percentage is calculated by calibration curve equation.Measurement result is as shown in Figure 5.
Relative to bulk drug, the dissolving out capability of ultrafine dust is significantly improved, and is embodied in, by 4h dissolution rate Detection, the dissolution rate of ultrafine dust can reach nearly 90%, and bulk drug dissolution rate is less than 50%.
Discussion of results
The embodiment is using acetone and ethanol as mixed solvent, volume ratio 1:1, using supercritical CO2Anti-solvent method prepares female Glycol particulate, in CO2Under conditions of exhaust volumetric flow 3L/min, baicalein particulate is prepared using Orthogonal Experiment and Design optimization Technique, obtained optimum condition are liquor capacity flow 1.0mL/min, crystallization pressure 14MPa, 40 DEG C of crystallization temperature, estradiol Mass concentration 8mg/mL.The estradiol particulate volume average particle size that selection process obtains is 7.36 μm, and the particle diameter of bulk drug is 50~60 μm, diameter of aspirin particle is obviously reduced；Equilbrium solubility of the before processing estradiol in water is extremely low, only 1.44 μ g/mL, and The ultrafine dust equilbrium solubility of selection process can reach 4.378 μ g/mL, improve three times or so；It is ultra-fine relative to bulk drug The dissolving out capability of particulate is significantly improved, and is embodied in, and is detected by 4h dissolution rate, the dissolution rate of ultrafine dust is reachable To nearly 90%, and bulk drug dissolution rate is less than 50%.
Embodiment 3
A kind of method that Supercritical anti-solvent prepares estradiol ultrafine dust, comprises the following steps：
Step S1, estradiol is dissolved in organic solvent, obtains estradiol solution, mass concentration 6mg/mL；
Step S2, by CO2It is passed through with 3L/min flow velocity in crystallization kettle, regulation crystallization temperature in the kettle is 55 DEG C, and pressure is 8MPa；
Step S3, continue to be passed through CO with 3L/min flow velocity2, maintain the temperature and pressure in crystallization kettle constant, simultaneously will Estradiol solution prepared by step S1 is passed through in crystallization kettle with 1.0mL/min volume flow；
Step S4, after estradiol solution is passed through, it is continually fed into CO2, maintain the temperature and pressure in crystallization kettle constant, Release after 40 minutes；After pressure is down to atmospheric pressure in crystallization kettle, opens crystallization kettle and collect estradiol ultrafine dust；
Wherein, sequencing is not present in step S1 and step S2；The organic solvent is the mixed solvent of acetone and ethanol, The two is according to volume ratio 1:1 mixing.
The average grain diameter of estradiol ultrafine dust prepared by above-mentioned steps is 3.46 μm.
The preparation method of the embodiment is unexpected gained：It is 55 DEG C to crystallize temperature in the kettle, should it can be seen from experiment of single factor At a temperature of obtained product in moist, viscous pasty state, dry solia particle, under normal circumstances, art technology can not be made Temperature will not be set to 55 DEG C by personnel.But by reducing crystallization pressure and estradiol concentration of polymer solution after, can not only make The estradiol particulate that must be dried, and obtained estradiol diameter of particle is smaller, also different from the variation tendency of experiment of single factor.
Embodiment 4
A kind of method that Supercritical anti-solvent prepares estradiol ultrafine dust, comprises the following steps：
Step S1, estradiol is dissolved in organic solvent, obtains estradiol solution, mass concentration 6mg/mL；
Step S2, by CO2It is passed through with 3L/min flow velocity in crystallization kettle, regulation crystallization temperature in the kettle is 55 DEG C, and pressure is 8MPa；
Step S3, continue to be passed through CO with 3L/min flow velocity2, maintain the temperature and pressure in crystallization kettle constant, simultaneously will Estradiol solution prepared by step S1 is passed through in crystallization kettle with 1.0mL/min volume flow；
Step S4, after estradiol solution is passed through, it is continually fed into CO2, maintain the temperature and pressure in crystallization kettle constant, Release after 40 minutes；After pressure is down to atmospheric pressure in crystallization kettle, opens crystallization kettle and collect estradiol ultrafine dust；
Wherein, sequencing is not present in step S1 and step S2；The organic solvent is the mixed solvent of ethanol and acetone, The two is according to volume ratio 1:2 mixing.
The average grain diameter of estradiol ultrafine dust prepared by above-mentioned steps is 1.53 μm.
The embodiment is the further optimization of embodiment 3, has changed the solvent of embodiment 3 into ethanol and acetone volume ratio 1: 2 mixed solvent.It can be seen from experiment of single factor, after acetone ratio increase, estradiol diameter of particle can increase, but in the reality Apply in example, as a result on the contrary, obtained estradiol diameter of particle is smaller.
The effect of above-described embodiment is only that the essentiality content of the explanation present invention, but the guarantor of the present invention is not limited with this Protect scope.It will be understood by those within the art that technical scheme can be modified or equally replaced Change, without departing from the essence and protection domain of technical solution of the present invention.

Claims (10)

  1. A kind of 1. method that estradiol ultrafine dust is prepared using Supercritical anti-solvent, it is characterised in that comprise the following steps：
    Step S1, estradiol is dissolved in organic solvent, obtains estradiol solution；
    Step S2, by CO2It is passed through in crystallization kettle, adjusts the temperature and pressure in crystallization kettle；
    Step S3, continue to be passed through CO with certain flow rate2, maintain the temperature and pressure in crystallization kettle constant, while prepared by step S1 Estradiol solution be passed through in crystallization kettle；
    Step S4, after estradiol solution is passed through, it is continually fed into CO2, maintain the temperature and pressure in crystallization kettle constant, one section Release after time；After pressure is down to atmospheric pressure in crystallization kettle, opens crystallization kettle and collect estradiol ultrafine dust；
    Wherein, sequencing is not present in step S1 and step S2；The organic solvent is the mixed solvent of acetone and ethanol.
  2. 2. according to the method for claim 1, it is characterised in that：The organic solvent is the mixed solvent of acetone and ethanol, The two is according to volume ratio 1:1 mixing.
  3. 3. according to the method for claim 2, it is characterised in that：The mass concentration of estradiol solution is 6-10mg/mL.
  4. 4. according to the method for claim 2, it is characterised in that：Temperature in step S2 regulation crystallization kettles is to 35-50 DEG C, pressure Power is to 8-18MPa.
  5. 5. according to the method for claim 2, it is characterised in that：Step S3 maintains CO2The flow velocity that is passed through be 2-4L/min.
  6. 6. according to the method for claim 2, it is characterised in that：Estradiol solution is passed through the volume flow of crystallization kettle in step S3 Measure as 0.6-1.4mL/min.
  7. 7. according to the method for claim 2, it is characterised in that：It is 0.5-2h for a period of time described in step S4.
  8. 8. according to the method for claim 2, it is characterised in that：The mass concentration of estradiol solution is 8mg/mL；CO2It is passed through The flow velocity of crystallization kettle is 3L/min；It is 40 DEG C to crystallize temperature in the kettle, pressure 14MPa；The volume flow of estradiol solution is 1.0mL/min；Release after 40 minutes.
  9. 9. according to the method for claim 2, it is characterised in that：The mass concentration of estradiol solution is 6mg/mL；CO2It is passed through The flow velocity of crystallization kettle is 3L/min；It is 55 DEG C to crystallize temperature in the kettle, pressure 8MPa；The volume flow of estradiol solution is 1.0mL/min；Release after 40 minutes.
  10. 10. according to the method for claim 1, it is characterised in that：The organic solvent is the mixed solvent of ethanol and acetone, The two is according to volume ratio 1:2 mixing；The mass concentration of estradiol solution is 6mg/mL；CO2The flow velocity for being passed through crystallization kettle is 3L/ min；It is 55 DEG C to crystallize temperature in the kettle, pressure 8MPa；The volume flow of estradiol solution is 1.0mL/min；Unloaded after 40 minutes Pressure.
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