A kind of micro passage reaction
Technical field
The present invention relates to a kind of micro passage reactions, belong to high molecular polymer microsphere preparation technology field.
Background technique
Mono-disperse polymer polymer microballoon has the appearance structure of uniform partial size and rule, is widely used in medicine
Object targets controllable sustained-release carrier, template, adsorption separating agent etc., and especially PVA microballoon is due to excellent chemically and thermally stable
Property, chemical modifiability, biocompatibility etc. have a wide range of applications in fields such as medicine, material, electronics.With PVA oligomer
Emulsification and cross linked polymerization preparation PVA microballoon has the characteristics that simple preparation process, process control, cost of material are cheap, is original with it
Material prepares uniform particle diameter, the PVA microballoon of good sphericity has become the research hotspot of people.
CN105462915A discloses a kind of preparation method of polyvinyl alcohol microparticles, and this method passes through inverse suspension for poly- second
Enolate solution is dispersed into spherical small liquid grain in oily phase, then adds crosslinking agent and is crosslinked to polyvinyl alcohol, by solidifying,
Washing and screening obtain polyvinyl alcohol microparticles, and microsphere supported partial size is 60-250 μm.The microspherulite diameter that this method obtains is difficult
Accurately to control, size distribution is inhomogenous, in addition, the technique is to be initially formed polyvinyl alcohol drop, adds acid for adjusting pH value, so
After add crosslinking agent carry out crosslinking curing, this following drawback of technique being added step by step: (1) acid and crosslinking agent need first to expand
The oil-water interfacial film across droplet surface is dissipated, is then reacted again with the polyvinyl alcohol in drop, and diffusion velocity is very slow, causes whole
A solidification process is very slow;(2) acid and crosslinking agent be diffused from outside to inside, so, the cross-linking reaction in drop is also by outer
Inwards, outside is formed by curing hard shell, and the acid and crosslinking agent of outside cannot continue across hard shell and react with the polyvinyl alcohol in drop,
Cause micro-sphere structure inhomogenous.
CN104857576A discloses a kind of method for preparing Polyvinyl Alcohol Embolization microballoon, the process route that this method uses
Are as follows: (1) polyvinyl alcohol water solution and cross-linking agent aqueous solution mixed solution are prepared as discrete phase 1, are prepared catalyst aqueous solution and are made
For discrete phase 2, preparing organic solvent incompatible with water is continuous phase;(2) hydrodynamic shear in microchannel and interface are utilized
Discrete phase is divided into drop by power effect;(3) after drop is collected, 0.5-24 hours progress crosslinking curings are stood at 20-80 DEG C,
Obtain granule of polyvinyl alcohol;(4) it by organic solvent washings such as cable type extractor according alkane, petroleum ether, ethyl acetate, and washs
Time is 12-48 hours, and polyvinyl alcohol microparticles production is dried to obtain under the techniques such as vacuum drying, freeze-drying or spray drying
Product.Although this method can prepare the PVA microballoon of homogeneous grain diameter, good sphericity, curing time is too long, and solidification temperature is high,
Washing process is complicated.
Summary of the invention
In order to solve the above technical problems, the purpose of the present invention is to provide a kind of micro passage reaction, it is special by being arranged
Quick, the controllable preparation of high molecular polymer microballoon at room temperature are realized in fluid convection mixed zone in the liquid of property.
In order to achieve the above objectives, the present invention provides a kind of micro passage reaction, which includes that drop produces
Fluid convection mixed zone, drop precrosslink curing area in raw area, drop;
Wherein, the channel of fluid convection mixed zone includes beeline channel and non-linear channels in the drop, described non-straight
Line passage is the bending channel of S type bending channel, Z-type channel or other irregular shapes.
In above-mentioned micro passage reaction, it is preferable that fluid convection mixed zone meets the following conditions in the drop:
L=L1+L2;
Wherein, L is the total length of fluid convection mixed zone in drop, unit m;L1For the length of beeline channel, unit
For m;L2For the straight length of non-linear channels, unit m.
In micro passage reaction of the invention, drop generates area for making dispersed phase, continuous phase etc. be mutually mixed to be formed
Drop, the channel which generates area can be T-type microchannel, the total focus type channel of flowing or total flow pattern channel.
In micro passage reaction of the invention, fluid convection mixed zone is used to make to generate what area generated in drop in drop
Component in drop is quickly sufficiently mixed.The section start of fluid convection mixed zone in drop, the diameter phase of beeline channel
The diameter for generating the channel in area for drop becomes larger suddenly, and using the sudden enlargement of this nozzle (caliber), side can occur
Interlayer separates and generates whirlpool, promotes fluid mixing in drop;In non-linear channels part, each bending inflection point can be due to
Wall surface causes fluid flow rate inside and outside drop different the resistance of fluid, and fluid generates whirlpool in drop, promotes mixing.The present invention
Drop in fluid convection mixed zone can guarantee in drop that fluid is uniformly mixed, and drop does not rupture and does not melt simultaneously.Melt meaning simultaneously
Think of is two or three droplet coalescences into one.
In micro passage reaction of the invention, drop precrosslink curing area is for making drop carry out precuring, channel
Section can be rectangular, round, oval or other shapes.Drop precrosslink curing area of the invention can make fluid in drop
Precuring just occurs, has certain molding, but does not have completion of cure (if completion of cure, the microballoon after solidification is easy to be deposited on
In channel, blocking channel), drop smoothly can flow into collector unit from curing area, go on smoothly reaction.
Micro passage reaction provided by the invention can also include collecting curing area, for collecting the cured drop of precrosslink
And keep its fully crosslinked to obtain microballoon.Collecting curing area can be set receiving flask, pre- charge of oil phase fluid in receiving flask, collecting pipe
It protrudes under collection liquid liquid level, collects bottle sealing.
Two-phase fluid is substantially at laminar flow in straight channel, mix it is very slow, can be with by the way that channel is designed to bending channel
So that fluid is generated disturbance when flowing through bending channel, promotes its mixing.In micro passage reaction of the invention, fluid in drop
The bending that the non-linear channels part of convection current mixed zone can be S type bending channel, Z-type channel or other irregular shapes is logical
Road.Length with channel direction the variation frequency of occurrence of fluid convection mixed zone are related in drop, that is, number of bends is related.It is logical
When the every generation one-shot change in road direction, chaotic advection will occur in drop for fluid in drop, and fluid in drop is caused to mix
Enhancing, mixing efficiency improve, and reach and are thoroughly mixed the time used and will shorten.Therefore, number of bends is more, and mixed zone channel is long
It spends short;Number of bends is few, and mixed zone passage length is long.
In micro passage reaction of the invention, S type bending channel is preferably by N number of end to end arc-shaped curvature portion group
At, and the value of N is not limited to integer, and specific value can be determined according to the length of required S type bending channel.It is preferred that
Ground, S type bending channel meet the following conditions:
R1For the outer diameter of arc-shaped curvature portion, unit m;R1Preferably 200-2000 microns;
R2For the internal diameter of arc-shaped curvature portion, unit m;R2Preferably 100-1000 microns;
θ is the corresponding central angle of arc-shaped curvature portion, it is preferable that 90 ° of 360 ° of < θ <, such as 135 °, 180 ° or 235 °, on
The corresponding S type bending channel of angle is stated respectively as shown in Fig. 1 a, Fig. 1 b, Fig. 1 c.
In micro passage reaction of the invention, Z-type channel is preferably made of M end to end Z-shaped bending sections, here
Z-shaped be not limited toIt is this common Z-shaped, there can also be extension, it is preferable that each Z-shaped bending section is by first point
Section, the second segmentation, third segmentation and the 4th segmentation composition, also, the first segmentation of the first Z-shaped bending section can be directly as liquid
The beeline channel of fluid convection mixed zone in dripping.The total length of non-linear channels can determine according to actual needs, therefore, finally
One Z-shaped bending section, which can be, can also completely only include the first segmentation, the second segmentation, the 1-3 in third segmentation.
Preferred embodiment according to the present invention, it is preferable that the first segmentation is with the second sectional vertical or at 90-150 °
Angle, the second segmentation are mutually perpendicular to third segmentation or at 90-150 ° of angles, and third segmentation is segmented with the 4th to be mutually perpendicular to
Or at 90-150 ° of angle;Above-mentioned angle is preferably 120-150 °, more preferably 90 °, 120 °, 135 ° or 150 °;Vertical
It may is that:Corresponding Z-type bending channel is as shown in Figure 2;Angled situation may is thatTool
Body angle is not limited to angle shown in above-mentioned figure.
Preferred embodiment according to the present invention, the first segmentation, the second segmentation, the third segmentation and the 4th of Z-shaped bending section
The length of segmentation is respectively 200-1500 microns, 300-2000 microns, 300-1500 microns, 200-2000 microns.
Preferred embodiment according to the present invention, Z-shaped bending section meet the following conditions: the angle between each segmentation is
90 °, also, the equal length of the first segmentation, the second segmentation, third segmentation and the 4th segmentation.
In micro passage reaction of the invention, it is preferable that the width that the drop generates the channel in area is that 50-500 is micro-
Meter, the width in the channel of fluid convection mixed zone is 100-1000 microns in the drop, drop precrosslink curing area
The width in channel is 1000-20000 microns.
In micro passage reaction of the invention, it is preferable that fluid convection mixed zone, drop in drop generation area, drop
The height in the channel of precrosslink curing area is identical, is 50-1500 microns.
In micro passage reaction of the invention, it is preferable that the length that the drop generates the channel in area is that 100-500 is micro-
Rice.
In micro passage reaction of the invention, the section start of fluid convection mixed zone, can use caliber in drop
Sudden enlargement promote drop in fluid mixing, it is preferable that in the drop width in the channel of fluid convection mixed zone with
The ratio between the width in channel that the drop generates area is 1-4:1 and is not 1:1, may be controlled to 1.5-4:1, more preferably 2-3:
1。
In micro passage reaction of the invention, it is preferable that the width in the channel of drop precrosslink curing area and institute
Stating the ratio between width in channel of fluid convection mixed zone in drop is 1-20:1, more preferably 1-15:1.
In micro passage reaction of the invention, it is preferable that the channel of the height in the channel and drop generation area
The ratio between width be 0.3-1.5:1.
In micro passage reaction of the invention, it is preferable that convection current mixed zone in the height in the channel and the drop
The ratio between the width in channel be 0.5-1.5:1.
In micro passage reaction of the invention, it is preferable that the length in the channel of fluid convection mixed zone in the drop
It is 1000-100000 microns, more preferably 5000-50000 microns.
In micro passage reaction of the invention, it is preferable that the length L3 in the channel of drop precrosslink curing area is
1000-10000 microns.
In micro passage reaction of the invention, material used in the channel of each section can be dimethyl silicone polymer
(PDMS), it is also possible to PMMA.
Micro passage reaction provided by the invention mainly has the advantages that
(1) the structure simple possible of micro passage reaction of the invention, the Microsphere Size that size adjustable is controllable, prepared can
Conveniently regulating and controlling, such as: using the size tunable of the monodisperse polyvinyl alcohol microparticles of micro passage reaction preparation of the invention, spherical shape
It spends, homogeneous grain diameter.
(2) fluid convection mixed zone can make stream in each drop in the drop being arranged in micro passage reaction of the invention
Body can be rapidly achieved in seconds and be thoroughly mixed, and can be made by the length in fluid convection mixed zone channel in regulation drop
Fluid realization is thoroughly mixed without precrosslink reaction occurs in hybrid channel in drop, and it is smooth to influence reaction for blocking channel
It carries out.
(3) the drop precrosslink curing area being arranged in micro passage reaction of the invention can be such that the component in drop occurs
Precrosslink reaction, forms basic gel structure, keeps preferable monodispersity and perfect sphericity to mention for the microballoon of preparation
Necessary precondition is supplied.
(4) it is different from traditional reaction unit, low energy consumption, serialization behaviour may be implemented in micro passage reaction of the invention
Make, yield can be quicklyd increase if by the simple parallel connection of multiple micro passage reactions, improves production efficiency, no any amplification effect
It answers.
In conclusion work of the existing technology can be overcome by preparing microballoon using micro passage reaction provided by the invention
The disadvantages of skill is complicated, product granularity is difficult to control accurately, pattern is irregular, and preparation process is simple, quick, and microballoon has grain
The advantages that diameter is controllable, homogeneous grain diameter, good sphericity.
Detailed description of the invention
Fig. 1 a, Fig. 1 b, Fig. 1 c be different angle corresponding S type bending channel schematic diagram.
Fig. 2 is the structural schematic diagram of the micro passage reaction with Z-type bending channel.
Fig. 3 is the micro passage reaction structural schematic diagram that comparative example 3 uses.
Fig. 4 is the micro passage reaction structural schematic diagram that embodiment 1 uses.
Fig. 5 is the scanning electron microscope (SEM) photograph of the monodisperse polyvinyl alcohol microparticles in embodiment 1, and scale is 100 μm.
Fig. 6 is the scanning electron microscope (SEM) photograph of the monodisperse polyvinyl alcohol microparticles in embodiment 2, and scale is 200 μm.
Fig. 7 is the scanning electron microscope (SEM) photograph of the fibert shaped polyethylene alcohol microballoon in embodiment 3, and scale is 200 μm.
Fig. 8 is the scanning electron microscope (SEM) photograph of the polyvinyl alcohol microparticles in embodiment 4, and scale is 500 μm.
Fig. 9 is the polyvinyl alcohol microparticles optical microscopy map in comparative example 3, and scale is 200 μm.
Figure 10 is the optical microscopy map of the polyvinyl alcohol gel microballoon in comparative example 4, and scale is 500 μm.
Figure 11 is polyvinyl alcohol gel microsphere optical micrograph after the drying in comparative example 4, and scale is 200 μm.
Specific embodiment
In order to which technical characteristic of the invention, purpose and beneficial effect are more clearly understood, now to skill of the invention
Art scheme carries out described further below, but should not be understood as that limiting the scope of the invention.
Embodiment 1
A kind of micro passage reaction is present embodiments provided, structure is as shown in Figure 4.
The micro passage reaction includes that drop generates area, fluid convection mixed zone, drop precrosslink curing area in drop,
In:
The width that drop generates the channel in area is 100 microns, is highly 150 microns, is flow focusing type microchannel, packet
Include two dispersed phase channels, two continuous phase channels;
The length L in the channel of fluid convection mixed zone is 6654 microns, width W in drop1For 200 microns, be highly 150
Micron,
The length L in the channel of drop precrosslink curing area3For 4000 microns, width W2For 1000 microns, be highly 150 micro-
Rice;
The channel of fluid convection mixed zone includes beeline channel and non-linear channels in drop, and non-linear channels are S type
Bending channel;The length L of beeline channel1It is 1000 microns, the length L of non-linear channels2It is 5654 microns;
The S type bending channel includes 3 regular end to end arc-shaped curvature portions, the outer diameter R of the arc-shaped curvature portion1For
700 microns, internal diameter R2It is 500 microns, corresponding central angle θ is 180 °.
Micro passage reaction provided by the present embodiment can be used for preparing monodisperse polyvinyl alcohol microparticles but not limited to this,
It can be followed the steps below when preparing monodisperse polyvinyl alcohol microparticles:
2.0g cetyl/- 10/1 dimethyl siloxane of polypropylene glycol (EM90) is added to the burning for being contained with 100mL mineral oil
It in cup, is slowly stirred by the way of magnetic agitation, then by filtering, obtains continuous phase solution;
By 2 grams of alcoholysis degrees be 97%, the polyvinyl alcohol that molecular weight is 100,000 is dissolved in 100 grams of water, obtains the first dispersed phase
Solution;
By 10 gram mass percentage compositions be 50% glutaraldehyde solution, 8 milliliters of molar concentrations be 10mol/L hydrochloric acid be mixed into
In 92 grams of water, the second dispersed phase solution is obtained;
Continuous phase solution, the first dispersed phase solution, the second dispersed phase solution are respectively charged into the syringe of 20mL, are placed in
On micro-injection pump, and it is connected with micro passage reaction, the flow velocity that the first dispersed phase solution and the second dispersed phase solution is arranged is equal
For 0.5mL/h, the flow velocity of continuous phase solution is 5mL/h, generates the drop of dispersed phase and continuous phase in micro passage reaction
Area channel intersection meets, and is continuously generated the Water-In-Oil drop of size uniformity, and solution component is polyvinyl alcohol, glutaraldehyde in drop
And hydrochloric acid;
Drop solidifies 20 points behind fluid convection mixed zone in drop and drop precrosslink curing area in receiving flask
Clock obtains polyvinyl alcohol microparticles;
After washing the polyvinylalcohol microsphere 5 times with dehydrated alcohol cooperation ultrasonic cleaning, monodisperse polyvinyl alcohol microparticles are obtained,
Partial size is 40 ± 2 microns, and Microsphere Size deviation is 1.26%, and scanning electron microscopic picture is shown in Fig. 5, it is seen that the homogeneous grain diameter of microballoon, ball
Shape degree is good.
Comparative example 1
This comparative example provides a kind of micro passage reaction, structure and the basic phase of micro passage reaction in embodiment 1
Together, the difference is that: the length in the channel of fluid convection mixed zone is 25000 microns in drop, width is 200 microns, high
Degree is 150 microns.
Monodisperse polyvinyl alcohol is prepared according to the step in embodiment 1 using micro passage reaction provided by this comparative example
Microballoon, difference are: when experiment carries out 10 minutes, having solid matter to be blocked in the channel of mixed zone, taking-up is viewed as linear poly-
Alcohol fibers.The length in the channel of fluid convection mixed zone is in the drop of the comparative example far more than embodiment 1, this comparative example
Result illustrate that the length in the channel of fluid convection mixed zone in drop is too long and be not suitable for preparing microballoon.
Comparative example 2
This comparative example provides a kind of micro passage reaction, structure and the basic phase of micro passage reaction in embodiment 1
Together, the difference is that: the length in the channel of fluid convection mixed zone is 10000 microns in drop, width is 1000 microns, high
Degree is 150 microns.
Monodisperse polyvinyl alcohol is prepared according to the step in embodiment 1 using micro passage reaction provided by this comparative example
Microballoon, difference are: when experiment carries out 15 minutes, having solid matter to be blocked in the connection between precrosslink curing area and receiving flask
In conduit, taking-up is viewed as linear polyethylene alcohol fiber.The width in the channel of fluid convection mixed zone in the drop of the comparative example
Greater than embodiment 1, the result of this comparative example illustrates that the width in the channel of fluid convection mixed zone in drop is wide and is not suitable for
Prepare microballoon.
Embodiment 2
A kind of micro passage reaction is present embodiments provided, structure is as shown in Figure 2.
The micro passage reaction includes that drop generates area, fluid convection mixed zone in drop, drop precrosslink curing area, receives
Collect bottle (not shown), in which:
The width that drop generates the channel in area is 300 microns, is highly 300 microns, for T-type microchannel, including two
Dispersed phase channel, two continuous phase channels;
The length in the channel of fluid convection mixed zone is 13000 microns in drop, width is 700 microns, it is micro- to be highly 300
Rice,
The length in the channel of drop precrosslink curing area is 6000 microns, width is 5600 microns, is highly 300 microns;
The Z-type bending channel includes 3 regular end to end Z-shaped bending sections, which includes being sequentially connected
The first segmentation, the second segmentation, third segmentation and the 4th segmentation, adjacent segmentation is mutually perpendicular to, the length difference of four segmentations
It is 1000 microns, 1300 microns, 733 microns, 1300 microns.
Micro passage reaction provided by the present embodiment can be used for preparing monodisperse polyvinyl alcohol microparticles but not limited to this,
It can be followed the steps below when preparing monodisperse polyvinyl alcohol microparticles:
2.0g cetyl polyethylene glycol (EM90) addition is contained in the beaker of 100mL mineral oil, using magnetic agitation
Mode be slowly stirred, then by filtering, obtain continuous phase solution;
By 2 grams of alcoholysis degrees be 97%, the polyvinyl alcohol that molecular weight is 100,000 is dissolved in 100 grams of water, obtains the first dispersed phase
Solution;
By 10 gram mass percentage compositions be 50% glutaraldehyde solution, 8 milliliters of molar concentrations be 10mol/L hydrochloric acid be mixed into
In 92 grams of water, the second dispersed phase solution is obtained;
Continuous phase solution, the first dispersed phase solution, the second dispersed phase solution are respectively charged into the syringe of 20mL, are placed in
On micro-injection pump, and it is connected with micro passage reaction, the flow velocity that the first dispersed phase solution and the second dispersed phase solution is arranged is equal
For 0.5mL/h, the flow velocity of continuous phase solution is 2mL/h, generates the drop of dispersed phase and continuous phase in micro passage reaction
Area channel intersection meets, and is continuously generated the Water-In-Oil drop of size uniformity, and solution component is polyvinyl alcohol, glutaraldehyde in drop
And hydrochloric acid;
Drop solidifies 20 points behind fluid convection mixed zone in drop and drop precrosslink curing area in receiving flask
Clock obtains polyvinyl alcohol microparticles;
After washing the polyvinylalcohol microsphere 5 times with dehydrated alcohol cooperation ultrasonic cleaning, monodisperse polyvinyl alcohol microparticles are obtained,
Partial size is 180 ± 10 microns, and scanning electron microscopic picture is shown in Fig. 6, it is seen that homogeneous grain diameter, the sphericity of microballoon are good.
Embodiment 3
Monodisperse polyvinyl alcohol is prepared according to the step in embodiment 2 using micro passage reaction provided by embodiment 2
Microballoon, difference are: the preparation of continuous phase solution are as follows: it is uniform that 5.0 grams of sorbester p17s are added to 100mL mineral oil, as
Continuous phase solution.The polyvinyl alcohol microparticles that experiment obtains are fibert shape, and partial size is 160 ± 10 microns.Its scanning electron microscope (SEM) photograph is shown in
Fig. 7.
Embodiment 4
Present embodiments provide a kind of micro passage reaction, structure and the basic phase of micro passage reaction in embodiment 2
Together, the difference is that: the length in the channel of fluid convection mixed zone is 3000 microns in drop, width is 700 microns, height
It is 300 microns.
Monodisperse polyvinyl alcohol is prepared according to the step in embodiment 4 using micro passage reaction provided by the present embodiment
Microballoon, polyvinyl alcohol microparticles obtained are the irregular graininess of concave-convex surface, and partial size is 180 ± 40 microns.It is scanned
Electron microscope is shown in Fig. 8.
Comparative example 3
This comparative example provides a kind of micro passage reaction, and only drop generates area, without other two functional areas, structure
As shown in figure 3, other solution are prepared and drop generates fluid flow rate control parameter with embodiment 1, then directly lead to after drop generates
It crosses conduit and introduces receiving flask, carry out crosslinking curing 72h, drop demulsification in solidification process, partial agglomeration is to together, after the completion of solidification
Microsphere particle rough surface, size distribution are inhomogenous, have partial particulate to be sticked together, and optical microscopy map is shown in Fig. 9.
Comparative example 4
This comparative example provides a kind of preparation method of monodisperse polyvinyl alcohol microparticles, wherein polyvinyl alcohol uses alcoholysis
Degree 85%, the raw material that molecular weight is 30000-70000 is made into the aqueous solution that mass percentage is 3%, and other all parameters are same
Embodiment 1 after introducing receiving flask by conduit, carries out crosslinking curing for 24 hours, and the transparent polyvinyl alcohol for obtaining uniform particle diameter is solidifying
Glue, having a size of 385 ± 10 microns, microoptic micrograph is shown in Figure 10.Continue crosslinking curing 120h, is still transparent
Polyvinyl alcohol gel, optical microscopy map is shown in Figure 11 after drying.
Compared with comparative example 3, above-described embodiment 2 rationally designed microreactor mixed zone and with curing molding area, make
It obtains various ingredients in drop and is able to quick, uniform mixing, guarantee the solidification rate of all directions and solidification when each drop solidifies
Degree is consistent, to obtain the microballoon of uniform particle diameter, good sphericity.
Compared with comparative example 4, above-described embodiment 2 use alcoholysis degree > 85%, molecular weight > 70000 polyvinyl alcohol for original
Material, reacts with glutaraldehyde and can get the higher degree of cross linking, and the microsphere surface after drying is more smooth, and sphericity is more preferable.