CN113332744B - Continuous crystallization micro-nano chemical chip and application thereof - Google Patents
Continuous crystallization micro-nano chemical chip and application thereof Download PDFInfo
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- CN113332744B CN113332744B CN202110584817.8A CN202110584817A CN113332744B CN 113332744 B CN113332744 B CN 113332744B CN 202110584817 A CN202110584817 A CN 202110584817A CN 113332744 B CN113332744 B CN 113332744B
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Abstract
The invention discloses a continuous crystallization micro-nano chemical chip and application thereof, comprising: the micro-nano chemical chip comprises a substrate and a cover plate covering the substrate, wherein a micro-mixing part is arranged on the substrate and is used for forming supersaturated mixed stock solution; the micro-dispersion part is communicated with the micro-mixing part, a flowing continuous phase is injected into the micro-dispersion part, the continuous phase and the supersaturated mixed stock solution are converged at the micro-dispersion part, and an acting force is continuously generated relative to the supersaturated mixed stock solution so that the supersaturated mixed stock solution is sheared into monodisperse liquid drops; the continuous crystallization part is provided with a preset length and is used for providing a place for the monodisperse liquid drops to continuously crystallize and form the monodisperse liquid drops wrapping the crystals, and a liquid film exists between the monodisperse liquid drops and the inner wall of the continuous crystallization part; the liquid drop is not infiltrated into the inner wall of the continuous crystallization part. The micro-nano chemical chip can realize continuous crystallization, provide uniform and stable crystallization conditions and avoid the phenomenon that the channel is blocked due to the adhesion and deposition of crystals on the wall surface of the channel.
Description
Technical Field
The invention relates to the field of crystallization equipment and technical research, in particular to a continuous crystallization micro-nano chemical chip and application thereof.
Background
Crystallization is one of the basic chemical processes and is also an important link for completing the production of chemical products. The crystallization process is not separated from the manufacturing and production of various chemical products, such as various petrochemical products, inorganic salts, polymers, building materials and the like, so that the crystallization is an indispensable important production process in modern industry. The crystal prepared by the traditional intermittent crystallization mode has larger grain diameter and uneven distribution. The increased grinding operation to reduce the crystal size destroys chemical bonds within the crystal and affects its quality, such as drug crystals and the like. And because the operation parameters such as material composition, temperature, pressure and the like in the generation process all change along with the time, the crystal quality difference among batches is easily caused. The continuous crystallization technology can realize continuous feeding and continuous discharging of raw materials, effectively reduce the crystallization production time, improve the utilization rate of the raw materials and improve the production efficiency. However, the inner wall of the channel or the pipeline of the existing continuous crystallizer is easy to generate crystal deposition and scaling, thereby blocking the channel and damaging a crystallization device. And the existing crystallization technology can not be rapidly applied to industrial production based on experimental results, and needs to be subjected to the process development processes of small test, pilot test and amplified production, so that the amplification effect exists.
Microfluidic technology is a technology that uses microchannels to manipulate or control the flow of a fluid, and its device is called a microfluidic chip. It is typically characterized by small three-dimensional dimensions, with channel dimensions on the micrometer-millimeter scale. Generally, compared with conventional equipment, the transfer efficiency of substances in the micro-nano chemical chip is improved by orders of magnitude compared with the mixing efficiency and the heat transfer efficiency. The microfluidic chip is applied to chemical engineering, so that the mixing efficiency is high, the heat transfer is fast, and the process can be continuous and is intrinsically safe. At present, typical applications of micro-nano chemical chips include micro-mixers, micro-separators, micro-detectors, micro-reactors and the like, and technologies for applying micro-nano chemical chips to crystallization are rarely reported.
Disclosure of Invention
The invention aims to solve the problems that the existing intermittent crystallization mode can not realize continuous production of products and the product quality is different among batches.
The invention also aims to solve the problem that the existing crystallization technology cannot be rapidly applied to industrial production based on experimental results and has amplification effect.
The invention also aims to solve the problem that the inner wall of a channel or the inner wall of a pipeline in the prior continuous crystallization technology is easy to have crystal scaling blockage and damage a crystallization device.
In order to achieve these objects and other advantages of the present invention, a continuous crystallization micro-nano chemical chip is provided, which comprises a substrate and a cover plate covering the substrate, wherein the substrate is provided with:
a micro-mixing section for forming a supersaturated mixed stock solution;
a micro-dispersion section which communicates with the micro-mixing section, and in which a continuous phase is injected, the continuous phase and the supersaturated mixed stock solution being merged at the micro-dispersion section, and the continuous phase generating a force against the supersaturated mixed stock solution so that the supersaturated mixed stock solution is sheared into monodisperse droplets;
the continuous crystallization part is provided with a preset length, and the monodisperse liquid drops are continuously crystallized in the continuous crystallization part to form monodisperse liquid drops wrapping crystals;
wherein a liquid film is arranged between the monodisperse liquid drop wrapped with the crystal and the inner wall of the continuous crystallization part, and the monodisperse liquid drop wrapped with the crystal is not infiltrated with the inner wall of the continuous crystallization part.
Preferably, the micro-mixing section includes:
one or more liquid injection channels which are communicated with the outside so as to inject one or more stock solutions, wherein the number of the liquid injection channels is consistent with the number of the stock solutions, and each stock solution is injected into the liquid injection channels at a first preset speed corresponding to the stock solution;
mixing channel, it with annotate the liquid channel intercommunication, be provided with a plurality of split units and a plurality of complex unit on the mixing channel, split unit with the complex unit sets up in succession in turn, the stoste passes through mixing channel forms supersaturation mixed stoste gets into in the microdispersion portion.
Preferably, the cover plate is made of transparent materials, and the thickness of the cover plate is 1-5 mm;
the thickness of the substrate is 1-5 mm, the width of the liquid injection channel is 200 mu m-3 mm, and the depth of the liquid injection channel is 200 mu m-3 mm.
Preferably, the first side of the micro-dispersion part is communicated with the micro-mixing part, the second side of the micro-dispersion part is communicated with the continuous crystallization part, and the third side of the micro-dispersion part is connected with a liquid inlet channel.
Preferably, the liquid inlet channel is disposed on the substrate, and the liquid inlet channel is used for injecting the continuous phase into the micro-dispersing part at a second preset speed, and has a width of 200 μm to 3mm and a depth of 200 μm to 3mm.
Preferably, the application method of the continuous crystallization micro-nano chemical chip comprises the following steps:
injecting one or more stock solutions into a micro-mixing part through one or more liquid injection channels, and generating supersaturated mixed stock solutions in the micro-mixing part through reaction crystallization, anti-solvent crystallization, cooling crystallization and other modes of the mixed stock solutions;
step two, the supersaturated mixed stock solution enters a micro-dispersion part from the tail end of the micro-mixing part, and simultaneously, the continuous phase is injected into the micro-dispersion part through a liquid inlet channel, so that the supersaturated mixed stock solution and the continuous phase are converged at the micro-dispersion part, and the flowing continuous phase generates acting force relative to the supersaturated mixed stock solution, so that the supersaturated mixed stock solution is sheared into monodisperse liquid drops;
step three, enabling the monodisperse liquid drops to enter a continuous crystallization part from the tail end of the micro-dispersion part, starting crystallization at the continuous crystallization part to form target crystals, nucleating and growing the target crystals in the monodisperse liquid drops, and continuously crystallizing the monodisperse liquid drops in the continuous crystallization part to form monodisperse liquid drops wrapping the crystals;
and step four, a liquid film exists between the monodisperse liquid drops wrapping the crystals and the inner wall of the continuous crystallization part in the step three, the monodisperse liquid drops wrapping the crystals are not soaked with the inner wall of the continuous crystallization part, and the monodisperse liquid drops wrapping the crystals continuously flow out from the tail end of the continuous crystallization part.
Preferably, in the first step, the number of the stock solutions is the same as the number of the liquid injection channels, each stock solution enters the mixing channel through the liquid injection channel corresponding to the stock solution, and each stock solution is injected into the liquid injection channel at a first preset speed corresponding to the stock solution.
Preferably, the continuous phase in step two is immiscible with the supersaturated mixed liquor, and the continuous phase is merged with the supersaturated mixed liquor at the micro-dispersion section at a second predetermined flow rate.
Preferably, the second step further comprises mixing a modifier with the continuous phase, injecting the mixture into the micro-dispersion part through the liquid inlet channel at a second preset flow rate, wherein the modifier is used for adjusting the interfacial tension between the continuous phase and the monodisperse liquid drop and the wettability of the inner wall of the continuous crystallization part to the monodisperse liquid drop wrapping the crystal.
Preferably, the modifier is miscible with the continuous phase and the modifier is immiscible with the supersaturated mixed stock solution.
The invention at least comprises the following beneficial effects:
1. the invention adopts the micro-nano chemical chip as the crystallizer, wherein the micro-nano chemical chip comprises a micron-millimeter flow channel, the high-efficiency and rapid mixing of the crystal reaction liquid, the crystal solution and the crystal anti-solvent can be realized, the uniform and stable supersaturated stock solution is generated, the phenomenon of uneven crystal quality caused by uneven solution mixing and supersaturation difference is avoided, the microchip-based crystallizer is subjected to quantity amplification in the process amplification process, the amplification effect is avoided, and the optimal reaction condition of laboratory pilot scale can be directly used for industrial production.
2. Compared with the traditional kettle type crystallization device, the micro-nano chemical chip has little liquid holdup which is in the milliliter level and has the characteristic of intrinsic safety. In addition, the micro-nano chemical chip has large specific surface area, high heat release and heat exchange efficiency, reaction and crystallization temperature can be easily controlled in the crystallization process, and the temperature inside the chip is uniformly distributed, so that crystals with uniform particle size distribution can be formed.
3. The crystallization process of the invention is carried out in monodisperse micro-droplets, a liquid film exists between the monodisperse droplets wrapping the crystals and the inner wall of the continuous crystallization part, and the monodisperse droplets wrapping the crystals are not infiltrated with the inner wall of the continuous crystallization part, so that the deposition and blockage of the crystals in the micro-channel can be prevented, and the application of the micro-nano chemical chip in the continuous crystallization technology can be realized.
4. The cover plate of the micro-nano chemical chip is made of transparent materials, so that the cover plate has the advantages of being convenient for an operator to observe crystallization and adjusting the flow rate of a solution in time, and in addition, the cover plate can prevent dust and the like from entering a channel of the micro-nano chemical chip, so that the crystal quality is improved.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a schematic structural diagram of a micro-nano chemical chip in embodiment 1 of the invention;
fig. 2 is a schematic structural diagram of a micro-nano chemical chip in embodiment 2 and embodiment 3 of the invention;
FIG. 3 is a flow chart of the crystallization of an anti-solvent in a Torilavir sodium micro-nano chemical chip in embodiment 2 of the invention;
FIG. 4 is a reaction crystallization flow diagram in a Torilavir sodium micro-nano chemical chip in embodiment 3 of the invention;
FIG. 5 is a schematic structural diagram of a monodisperse droplet coated with crystals and a continuous crystallization part according to the present invention.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
The invention provides a continuous crystallization micro-nano chemical chip which comprises a substrate and a cover plate covering the substrate, wherein the thickness of the substrate is 1-5 mm, the thickness of the cover plate is 1-5 mm, and the cover plate is made of a transparent material, so that an operator can observe the crystallization phenomenon conveniently to adjust the flow rate of a solution in time. The substrate is provided with: the micro-mixing part 1, the micro-dispersion part 2 and the continuous crystallization part 3, wherein the first side 21 of the micro-dispersion part is communicated with the micro-mixing part 1, the second side 22 of the micro-dispersion part is communicated with the continuous crystallization part 3, and the third side 23 of the micro-dispersion part is connected with the liquid inlet channel 4.
The micro-mixing part 1 is used for forming supersaturated mixed stock solution, the micro-mixing part 1 comprises one or more liquid injection channels 11 and a mixing channel 12, the liquid injection channels 11 are communicated with the outside so as to inject one or more stock solutions, the number of the liquid injection channels 11 is consistent with the number of the stock solutions, each stock solution is injected into the liquid injection channels 11 at a first preset speed corresponding to the stock solution, the width of each liquid injection channel 11 is 200 mu m-3 mm, and the depth of each liquid injection channel 11 is 200 mu m-3 mm. The mixing channel 12 is communicated with the liquid injection channel 11, the mixing channel 12 is provided with a plurality of splitting units 121 and a plurality of composite units 122, the splitting units 121 and the composite units 122 are continuously and alternately arranged, and stock solution forms supersaturated mixed stock solution through the mixing channel 12 and enters the micro-dispersion part 2. Because the micro-channel has smaller size, one or more stock solutions can be quickly and uniformly mixed, the concentration of reactants is uniform, and because of the larger specific surface area of the micro-mixing structure, the temperature in the channel is stable and uniform, and the change of reaction conditions in the mixing channel is avoided. The advantage overcomes the defects of non-uniform reactant concentration and unstable product quality caused by reaction temperature difference of the traditional kettle reactor.
The micro-dispersion part 2 is communicated with the micro-mixing part 1, a flowing continuous phase is injected in the micro-dispersion part 2, the continuous phase and the supersaturated mixed stock solution are converged at the micro-dispersion part 2, and an acting force is continuously generated relative to the supersaturated mixed stock solution so that the supersaturated mixed stock solution is sheared into monodisperse liquid drops.
The continuous crystallization part 3 has a preset length, and the monodisperse liquid drops are continuously crystallized in the continuous crystallization part 3 to form monodisperse liquid drops wrapping crystals; a liquid film 6 is present between the monodisperse droplet 5 coated with the crystal and the inner wall of the continuous crystallization section 3, and the monodisperse droplet 5 coated with the crystal is not wetted with the inner wall of the continuous crystallization section 3. The liquid film between the monodisperse liquid drop 5 wrapping the crystal and the inner wall of the continuous crystallization part 3 avoids the direct contact between the solid crystal and the inner wall of the continuous crystallization part 3, and prevents the crystal from depositing in the micro-channel. In addition, since the crystallization process occurs in the micro-scale monodisperse droplet, the number of crystals in the monodisperse droplet is small. Therefore, compared with the conventional crystallization equipment and technology, the invention obviously reduces the agglomeration among crystals.
The liquid inlet channel 4 is arranged on the substrate, the liquid inlet channel 4 is used for injecting the continuous phase or the mixed solution of the continuous phase and the modifier into the micro-dispersion part 2 at a second preset speed, the width of the liquid inlet channel 4 is 200 mu m-3 mm, and the depth of the liquid inlet channel 4 is 200 mu m-3 mm. The modifier is mixed with the continuous phase and the supersaturated mixed stock solution in the micro-dispersion part 2 and then flows into the continuous crystallization part 3 together, the modifier can adjust the interfacial tension and the wall surface wettability between the supersaturated mixed stock solution and the continuous phase, so that the formation of monodisperse liquid drops of the supersaturated mixed stock solution is facilitated, the monodisperse liquid drops and the inner wall of the continuous crystallization part 3 are not wetted and have liquid films, the formed monodisperse liquid drops 5 wrapping crystals smoothly flow out from the tail end of the continuous crystallization part 3, and the production efficiency is further improved.
Example 1
The micro-nano chemical engineering chip is provided with two liquid injection channels 11, as shown in figure 1, the liquid injection channel 11 on the left side is 300 micrometers deep, 520 micrometers wide and 10mm long; the right liquid injection channel 11 is 300 μm deep, 520 μm wide and 10mm long; the liquid inlet channel 4 is 300 mu m deep, 700 mu m wide and 25mm long; the continuous crystallization part 3 is 300 μm deep, 800 μm wide and 200mm long, the mixing channel 12 is 2mm long and comprises 2 splitting units 121 and 2 recombination units 122, and the base plate and the cover plate are glass plates with the thickness of 2 mm.
Firstly, placing the micro-nano chemical chip under a reaction condition that the environmental temperature is 20 ℃, then injecting a sodium hydroxide solution with the concentration of 4.5mol/L into the liquid injection channel 11 at the left side at the flow rate of 0.01ml/min, injecting a hydrochloric acid solution with the concentration of 4.5mol/L into the liquid injection channel 11 at the right side at the flow rate of 0.01ml/min, wherein a solvent of the sodium hydroxide and the hydrochloric acid solution adopts a mixed solution of water and ethanol, the ethanol content in the solvent is 45%, the sodium hydroxide solution and the hydrochloric acid solution flow through the mixed channel 12 together, and react at the mixed channel 12 to form a supersaturated mixed stock solution of sodium chloride;
step two, injecting a liquid paraffin solution containing 5% (V/V) of a compound surfactant into the liquid inlet channel 4 at a flow rate of 0.2ml/min as a continuous phase, wherein the compound surfactant in the continuous phase is a mixture of span 80 and tween, and the mixing mass ratio of the span 80 to the tween is 7.82; converging the supersaturated mixed stock solution of the sodium chloride in the first step at a T-shaped structure of a micro-dispersion part 2, shearing the supersaturated mixed stock solution of the sodium chloride into monodisperse liquid drops by utilizing T-shaped shearing, and regulating the size of the liquid drops of the monodisperse sodium chloride solution by regulating the flow rates of the sodium hydroxide solution, the hydrochloric acid and the paraffin wax solution;
step three, enabling the monodisperse liquid drops to enter a continuous crystallization part 3 from the tail end of a micro-dispersion part 2, starting crystallization at the continuous crystallization part 3 to form sodium chloride crystals, nucleating and growing the sodium chloride crystals in the monodisperse liquid drops, and finally enabling the monodisperse liquid drops to form monodisperse liquid drops wrapping the sodium chloride crystals in the continuous crystallization part 3, wherein a liquid film exists between the monodisperse liquid drops wrapping the sodium chloride crystals and the inner wall of the continuous crystallization part 3, and the liquid film component is a liquid paraffin solution containing 5% (V/V) of the compound surfactant;
step four, the crystallization process of the sodium chloride crystals occurs in the monodisperse liquid drops to form monodisperse liquid drops wrapping the sodium chloride crystals, the monodisperse liquid drops wrapping the sodium chloride crystals are not infiltrated into the inner wall of the continuous crystallization part 3, a liquid film between the monodisperse liquid drops wrapping the sodium chloride crystals and the inner wall of the continuous crystallization part 3 avoids direct contact of solid crystals and the wall surface, the crystals are prevented from depositing in the micro-channel, the crystallization process occurs in the liquid drops with a micro scale, the number of the crystals in the liquid drops is small, and the monodisperse liquid drops wrapping the sodium chloride crystals can smoothly and continuously flow out from the tail end of the continuous crystallization part 3.
Example 2
The micro-nano chemical chip is provided with two liquid injection channels 11, the structural schematic diagram is shown in figure 2, the liquid injection channel 11 on the left side is 200 microns deep, 800 microns wide and 14mm long; the right liquid injection channel 11 is 200 μm deep, 800 μm wide and 14mm long; the liquid inlet channel 4 is 200 μm deep, 800 μm wide and 68mm long; the continuous crystallization section 3 is 200 μm deep, 800 μm wide and 1000mm long, the mixing channel 12 is 5.6mm long and comprises 9 splitting units 121 and 9 recombination units 122, and the base plate and the cover plate are glass plates 2mm thick.
Firstly, placing the micro-nano chemical chip under a reaction condition that the ambient temperature is 25 ℃, then injecting 0.01g/ml of dorzolawir sodium solution into the left liquid injection channel 11 at the flow rate of 0.05ml/min, injecting isopropanol into the right liquid injection channel 11 at the flow rate of 0.05ml/min, enabling the isopropanol solution and the dorzolawir sodium solution to jointly flow through the mixing channel 12, and mixing at the mixing channel 12 to form supersaturated mixed stock solution of dorzolawir sodium. Due to the small size of the micro-channel, the doramevir sodium solution and the isopropanol can be quickly and uniformly mixed, so that the reactant concentration is uniform. The advantage overcomes the defect of unstable product quality caused by nonuniform concentration of reactants in the traditional tank reactor.
And step two, injecting a liquid paraffin solution containing 4wt% of span 20 into the liquid inlet channel 4 as a continuous phase at a flow rate of 0.2ml/min, converging the liquid paraffin solution with the supersaturated mixed stock solution of dortavir sodium in the step one at a T-shaped structure of the micro-dispersion part 2, shearing the supersaturated mixed stock solution of dortavir sodium into monodisperse droplets by utilizing T-shaped shearing, and regulating the size of the monodisperse dortavir sodium solution droplets by regulating the flow rates of the dortavir sodium solution, isopropanol and paraffin solution.
Step three, in the step two, the monodisperse liquid drops of the supersaturated doramevir sodium solution enter the continuous crystallization part 3 from the tail end of the micro dispersion part 2, crystallization is started at the continuous crystallization part 3 to form doramevir sodium crystals, the doramevir sodium crystals nucleate and grow in the monodisperse liquid drops of the supersaturated doramevir sodium solution, finally the monodisperse liquid drops form monodisperse liquid drops wrapping the doramevir sodium crystals in the continuous crystallization part 3, a liquid film exists between the monodisperse liquid drops wrapping the doramevir sodium crystals and the inner wall of the continuous crystallization part 3, and the component of the liquid film is the liquid paraffin solution containing 4wt% of span 20;
step four, the crystallization process of the dorawiravir sodium crystals occurs in the monodisperse liquid drops, so that the monodisperse liquid drops wrapping the dorawiravir sodium crystals are formed, the monodisperse liquid drops wrapping the dorawiravir sodium crystals are not soaked in the inner wall of the continuous crystallization part 3, the liquid film between the monodisperse liquid drops wrapping the dorawiravir sodium crystals and the inner wall of the continuous crystallization part 3 avoids the direct contact of the solid crystals and the inner wall of the continuous crystallization part 3, the crystals are prevented from depositing in the micro-channel, the crystallization process occurs in the liquid drops with the micro-scale, the number of the crystals in the liquid drops is small, and the monodisperse liquid drops wrapping the dorawiravir sodium crystals can smoothly and continuously flow out from the tail end of the continuous crystallization part 3. Compared with the conventional crystallization equipment and technology for the doramevir sodium, the method obviously reduces the agglomeration among the doramevir sodium crystals.
Example 3
The micro-nano chemical engineering chip is provided with two liquid injection channels 11, the structural schematic diagram is shown in figure 2, and the liquid injection channel 11 on the left side is 200 microns deep, 800 microns wide and 14mm long; the right liquid injection channel 11 is 200 μm deep, 800 μm wide and 14mm long; the liquid inlet channel 4 is 200 μm deep, 800 μm wide and 68mm long; the continuous crystallization section 3 is 200 μm deep, 800 μm wide and 444mm long, the mixing channel 12 is 5.6mm long and comprises 9 splitting units 121 and 9 recombination units 122, and the base plate and the cover plate are glass plates 2mm thick.
Firstly, placing the micro-nano chemical chip under the reaction condition that the environmental temperature is 70 ℃, then injecting 0.00865g/ml doramevir solution into the left liquid injection channel 11 at the flow rate of 0.05ml/min, injecting 0.019878g/ml sodium hydroxide into the right liquid injection channel 11 at the flow rate of 0.02ml/min, wherein the solvents of the sodium hydroxide and the doramevir solution respectively adopt water and isopropanol, the sodium hydroxide solution and the doramevir solution flow through the mixing channel 12 together, and react at the mixing channel 12 to form supersaturated mixed stock solution of the doramevir sodium. Because the micro-channel has smaller size, the doramevir solution and the sodium hydroxide solution can be quickly and uniformly mixed, so that the reactant concentration is uniform. And because the micro-mixing part 1 has a larger specific surface area, the temperature in the channel is stable and uniform, the change of reaction conditions in the channel of the micro-mixing part 1 is avoided, and the defects of non-uniform reactant concentration and unstable product quality caused by reaction temperature difference of the traditional kettle-type reactor are overcome.
And step two, injecting a liquid paraffin solution containing 4wt% of span 20 as a continuous phase into the liquid inlet channel 4 at a flow rate of 0.08ml/min, converging the liquid paraffin solution and the supersaturated mixed stock solution of the dortavir sodium in the step one at a T-shaped structure of the micro-dispersion part 2, and shearing the supersaturated mixed stock solution of the dortavir sodium into monodisperse liquid drops by utilizing T-shaped shearing. In addition, the size of the droplets of the monodisperse dorzolavir sodium solution can be regulated and controlled by regulating the flow rates of the dorzolavir solution, the sodium hydroxide solution and the paraffin wax solution.
Step three, in the step two, monodisperse liquid drops of supersaturated dortavir sodium solution enter a continuous crystallization part 3 from the tail end of a micro dispersion part 2, crystallization is started to form dortavir sodium crystals at the continuous crystallization part 3, the dortavir sodium crystals nucleate and grow in the monodisperse liquid drops of the supersaturated dortavir sodium solution, finally the monodisperse liquid drops form monodisperse liquid drops wrapping the dortavir sodium crystals in the continuous crystallization part 3, a liquid film exists between the monodisperse liquid drops wrapping the dortavir sodium crystals and the inner wall of the continuous crystallization part 3, and the component of the liquid film is a liquid paraffin solution containing 4wt% of span 20;
step four, the crystallization process of the dorawiravir sodium crystals occurs in the monodisperse liquid drops, so that the monodisperse liquid drops wrapping the dorawiravir sodium crystals are formed, the monodisperse liquid drops wrapping the dorawiravir sodium crystals are not soaked in the inner wall of the continuous crystallization part 3, the liquid film between the monodisperse liquid drops wrapping the dorawiravir sodium crystals and the inner wall of the continuous crystallization part 3 avoids the direct contact of the solid crystals and the inner wall of the continuous crystallization part 3, the crystals can be effectively prevented from depositing in the microchannel, the crystallization process occurs in the liquid drops in the microscale, the number of the crystals in the liquid drops is small, and the monodisperse liquid drops wrapping the dorawiravir sodium crystals can smoothly and continuously flow out from the tail end of the continuous crystallization part 3. Compared with the conventional dorawitworthia sodium crystallization equipment and technology, the present embodiment significantly reduces the agglomeration among dorawitavi sodium crystals.
Comparative example 1
The micro-nano chemical engineering chip is provided with two liquid injection channels 11, wherein the liquid injection channel 11 on the left side is 200 micrometers deep, 400 micrometers wide and 15mm long; the liquid injection channel 11 on the right side is 200 microns deep, 400 microns wide and 15mm long; the continuous crystallization part 3 is 200 μm deep, 400 μm wide and 500mm long, the micro-mixing part is of a T-shaped structure with a length of 0.5mm, the micro-mixing part 1 adopts a T-shaped mixing structure, and the substrate and the cover plate are glass plates with a thickness of 2 mm.
Firstly, placing the micro-nano chemical chip under the reaction condition that the environmental temperature is 70 ℃, then injecting a sodium hydroxide solution with the concentration of 0.01977g/ml into the liquid injection channel 11 on the left side at the flow rate of 0.01ml/min, injecting a dortiravir solution with the concentration of 0.0164g/ml into the liquid injection channel 11 on the right side at the flow rate of 0.02ml/min, wherein water and isopropanol are respectively adopted as a solvent of the sodium hydroxide and the dortiravir solution, the sodium hydroxide solution and the dortiravir solution flow through the mixing channel 12 together, and react at the mixing channel 12 to generate a supersaturated mixed stock solution of the dortiravir sodium. Because the T-shaped mixing effect is not strong, the concentration of the product of the doramevir sodium is not uniform, the local supersaturation degree is larger, a large number of crystal nuclei are formed in the micro-mixing part 1, and the crystal nuclei grow rapidly.
And step two, the supersaturated dorawitvir sodium solution grows in the micro-mixing part channel and the continuous crystallization part channel to form a dorawitvir sodium crystal, and the dorawitvir sodium crystal is discharged from the tail end of the continuous crystallization part 3. Since the homogeneous continuous reaction crystallization cannot avoid direct contact of the crystals with the inner wall of the channel, deposition and clogging of the crystals in the microchannel occur after about 5 minutes of continuous operation, and the continuous homogeneous reaction crystallization operation is stopped.
Comparative example 2
The micro-nano chemical chip is provided with two liquid injection channels 11, wherein the liquid injection channel 11 on the left side is 200 microns deep, 400 microns wide and 15mm long; the liquid injection channel 11 on the right side is 200 microns deep, 400 microns wide and 15mm long; the liquid inlet channel 4 is 200 μm deep, 400 μm wide and 68mm long; the continuous crystallization section 3 is 200 μm deep, 400 μm wide and 1030mm long, the mixing channel 12 is 3mm long and comprises 3 splitting units 121 and 3 recombination units 122, and the base plate and the cover plate are made of 2mm thick glass plates.
Firstly, placing the micro-nano chemical chip under a reaction condition that the ambient temperature is 70 ℃, injecting 0.009g/ml dortavir solution into the left liquid injection channel 11 at a flow rate of 0.00013ml/min, injecting 0.08g/ml sodium hydroxide solution into the right liquid injection channel 11 at a flow rate of 0.00013ml/min, wherein solvents of the sodium hydroxide and the dortavir solution respectively adopt water and isopropanol, the sodium hydroxide solution and the dortavir solution flow through the mixing channel 12 together, and react at the mixing channel 12 to generate supersaturated mixed stock solution of the dortavir sodium. The dorawivier solution and the sodium hydroxide solution flow through the mixing channel 12 together and react at the mixing channel 12 to generate the dorawivier sodium, so that a supersaturated solution of the dorawivier sodium is formed.
And step two, injecting the liquid paraffin solution serving as a continuous phase into the liquid inlet channel 4 at a flow speed of 0.005ml/min, converging the liquid paraffin solution and the supersaturated mixed stock solution of the dortavir sodium in the step one at a T-shaped structure of the micro-dispersion part 2, and dispersing the supersaturated mixed stock solution of the dortavir sodium by using the T-shaped structure. Because the wettability modification is not carried out on the wall surface of the channel and the interfacial tension between the paraffin solution and the supersaturated doramevir sodium solution is adjusted, the supersaturated doramevir sodium solution cannot be sheared into liquid drops in a micro-dispersion part and is dispersed in a slug flow mode.
And step three, in the step two, a slug of supersaturated dortavir sodium solution enters the continuous crystallization part 3 from the tail end of the micro dispersion part 2, crystallization is started to form a dortavir sodium crystal at the continuous crystallization part 3, and the dortavir sodium crystal nucleates and grows in the slug of the supersaturated dortavir sodium solution.
And step four, the slug is soaked with the inner wall of the continuous crystallization part 3, and no liquid film is isolated, so that the crystal of the dortavir sodium in the slug can directly contact with the inner wall of the continuous crystallization part 3, and the phenomena of adhesion, deposition and blockage of the crystal on the inner wall of the channel occur. After about 15 minutes of continuous operation, deposition and clogging of crystals in the microchannel occurred, and the continuous liquid-liquid heterogeneous reaction crystallization operation was stopped.
Comparative example 3
The micro-nano chemical chip is provided with two liquid injection channels 11, wherein the liquid injection channel 11 on the left side is 200 microns deep, 400 microns wide and 15mm long; the right liquid injection channel 11 is 200 μm deep, 400 μm wide and 15mm long; the liquid inlet channel 4 is 200 μm deep, 400 μm wide and 68mm long; the continuous crystallization section 3 is 200 μm deep, 400 μm wide and 1030mm long, the mixing channel 12 is 5.6mm long and comprises 9 splitting cells 121 and 9 recombination cells 122, and the base plate and the cover plate are 2mm thick glass plates.
Firstly, placing the micro-nano chemical chip under the reaction condition that the environmental temperature is 70 ℃, injecting 0.0175g/ml dortavir solution into the liquid injection channel 11 on the left side at the flow rate of 0.01ml/min, injecting 0.01986g/ml sodium hydroxide into the liquid injection channel 11 on the right side at the flow rate of 0.005ml/min, wherein the sodium hydroxide and the dortavir solution adopt water and isopropanol respectively as solvents, the sodium hydroxide solution and the dortavir solution flow through the mixing channel 12 together, and reacting at the mixing channel 12 to form supersaturated mixed stock solution of dortavir sodium. The dorawivier solution and the sodium hydroxide solution flow through the mixing channel 12 together and react at the mixing channel 12 to generate the dorawivier sodium, so that a supersaturated solution of the dorawivier sodium is formed.
And step two, injecting nitrogen with the air pressure of 0.15bar into the liquid inlet channel 4, converging the supersaturated mixed stock solution of the dorawitwei sodium in the step one at a T-shaped structure of the micro-dispersion part 2, and forming gas-liquid slug flow at the micro-dispersion part 2 by adjusting the pressure of the sodium hydroxide solution, the dorawitwei solution and the nitrogen, wherein the gas slug in the gas-liquid slug flow is a nitrogen slug flow, and the liquid slug flow is a supersaturated mixed stock solution slug flow of the dorawitwei sodium.
And step three, the supersaturated slug of the dorawitlavian sodium solution in the step two enters the continuous crystallization part 3 from the tail end of the micro dispersion part 2, crystallization is started at the continuous crystallization part 3 to form a dorawitlavian sodium crystal, and the dorawitlavian sodium crystal nucleates and grows in the supersaturated slug of the dorawitlavian sodium solution.
And step four, the slug is soaked with the inner wall of the continuous crystallization part 3, and no liquid film is isolated between the slug and the inner wall of the continuous crystallization part 3, so that the dorzolate sodium in the slug can directly contact with the inner wall of the continuous crystallization part 3, and the phenomena of crystal adhesion, deposition and blockage on the inner wall of a channel occur. In addition, due to the compressibility of the gas, the pressure fluctuation of the flow path of the liquid inlet channel 4 is large, and the aggregation between an unstable gas column and an unstable gas column is easy to occur, so that the retention time of crystals in the micro-channel is inconsistent. After about 17 minutes of continuous operation, deposition and clogging of crystals in the microchannel occurred, and continuous gas-liquid heterogeneous reaction crystallization operation was stopped.
While embodiments of the invention have been disclosed above, it is not intended to be limited to the uses set forth in the specification and examples. It can be applied to all kinds of fields suitable for the present invention. Additional modifications will readily occur to those skilled in the art. It is therefore intended that the invention not be limited to the exact details and illustrations described and illustrated herein, but fall within the scope of the appended claims and equivalents thereof.
Claims (9)
1. The continuous crystallization micro-nano chemical chip is characterized by comprising a substrate and a cover plate covering the substrate, wherein the substrate is provided with:
a micro-mixing section (1) for forming a supersaturated mixed stock solution;
a micro-dispersion unit (2) which communicates with the micro-mixing unit (1), and in which a continuous phase is injected into the micro-dispersion unit (2), the continuous phase and the supersaturated mixed stock solution join at the micro-dispersion unit (2), and the continuous phase exerts a force on the supersaturated mixed stock solution to shear the supersaturated mixed stock solution into monodisperse droplets;
a continuous crystallization part (3) with a preset length, wherein the monodisperse liquid drops are continuously crystallized in the continuous crystallization part (3) to form monodisperse liquid drops (5) wrapping crystals;
wherein a liquid film (6) exists between the monodisperse droplet (5) wrapping the crystal and the inner wall of the continuous crystallization part (3), and the monodisperse droplet (5) wrapping the crystal is not wetted with the inner wall of the continuous crystallization part (3);
the micro-mixing section (1) comprises:
one or more liquid injection channels (11) which are communicated with the outside so as to inject one or more stock solutions, wherein the number of the liquid injection channels (11) is consistent with the number of the types of the stock solutions, and each stock solution is injected into the liquid injection channels (11) at a first preset speed corresponding to the stock solution;
mixing channel (12), it with annotate liquid channel (11) intercommunication, be provided with a plurality of split unit (121) and a plurality of compound unit (122) on mixing channel (12), split unit (121) with compound unit (122) are continuous alternately to be set up, the stoste passes through mixing channel (12) forms supersaturation mixed stoste gets into in the little dispersion portion (2).
2. The continuous crystallization micro-nano chemical industry chip as claimed in claim 1, wherein the cover plate is made of transparent material, and the thickness of the cover plate is 1 to 5mm;
the thickness of the substrate is 1-5 mm, the width of the liquid injection channel (11) is 200 mu m-3 mm, and the depth of the liquid injection channel (11) is 200 mu m-3 mm.
3. The continuous crystallization micro-nano chemical chip according to claim 1, characterized in that a first side (21) of a micro-dispersion part is communicated with the micro-mixing part (1), a second side (22) of the micro-dispersion part is communicated with the continuous crystallization part (3), and a third side (23) of the micro-dispersion part is connected with a liquid inlet channel (4).
4. The continuous crystallization micro-nano chemical chip according to claim 3, wherein the liquid inlet channel (4) is disposed on the substrate, the liquid inlet channel (4) is used for injecting the continuous phase into the micro-dispersion part (2) at a second predetermined speed, the width of the liquid inlet channel (4) is 200 μm to 3mm, and the depth of the liquid inlet channel (4) is 200 μm to 3mm.
5. The application of the continuous crystallization micro-nano chemical engineering chip according to claim 1, characterized by comprising the following steps:
injecting one or more stock solutions into a micro-mixing part (1) through one or more liquid injection channels (11), and generating supersaturated mixed stock solutions in the micro-mixing part (1) through reaction crystallization, anti-solvent crystallization and cooling crystallization of the mixed stock solutions;
step two, the supersaturated mixed stock solution enters a micro-dispersion part (2) from the tail end of the micro-mixing part (1), meanwhile, the continuous phase is injected into the micro-dispersion part (2) through a liquid inlet channel (4), so that the supersaturated mixed stock solution and the continuous phase are converged at the micro-dispersion part (2), and the flowing continuous phase generates an acting force relative to the supersaturated mixed stock solution, so that the supersaturated mixed stock solution is sheared into monodisperse liquid drops;
step three, enabling the monodisperse liquid drops to enter a continuous crystallization part (3) from the tail end of a micro-dispersion part (2), starting crystallization at the continuous crystallization part (3) to form target crystals, wherein the target crystals nucleate and grow in the monodisperse liquid drops, and the monodisperse liquid drops continuously crystallize in the continuous crystallization part (3) to form monodisperse liquid drops (5) wrapping the crystals;
and step four, a liquid film (6) is arranged between the monodisperse droplet (5) wrapping the crystal and the inner wall of the continuous crystallization part (3) in the step three, the monodisperse droplet (5) wrapping the crystal is not soaked with the inner wall of the continuous crystallization part (3), and the monodisperse droplet (5) wrapping the crystal continuously flows out from the tail end of the continuous crystallization part (3).
6. The application of the continuous crystallization micro-nano chemical engineering chip according to claim 5, characterized in that in the first step, the number of the stock solutions is the same as the number of the liquid injection channels (11), each stock solution enters the mixing channel (12) through the liquid injection channel (11) corresponding to the stock solution, and each stock solution is injected into the liquid injection channel (11) at a first preset speed corresponding to the stock solution.
7. The application of the continuous crystallization micro-nano chemical industry chip according to claim 5, wherein the continuous phase in the second step is immiscible with the supersaturated mixed stock solution, and the continuous phase is merged with the supersaturated mixed stock solution at the micro-dispersion part (2) at a second predetermined flow rate.
8. The application of the continuous crystallization micro-nano chemical industry chip as claimed in claim 5, wherein the second step further comprises mixing and dissolving a modifier with the continuous phase, injecting the mixture into the micro-dispersion part (2) through the liquid inlet channel (4) at a second preset flow rate, wherein the modifier is used for adjusting the interfacial tension between the continuous phase and the monodisperse liquid drop and the wettability of the inner wall of the continuous crystallization part (3) to the monodisperse liquid drop (5) wrapping the crystal.
9. The application of the continuous crystallization micro-nano chemical chip in claim 8, wherein the modifier is mutually soluble with the continuous phase, and the modifier is not dissolved with the supersaturated mixed stock solution.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101479041A (en) * | 2006-06-28 | 2009-07-08 | 微溶解有限公司 | A device and a method for promoting crystallisation |
| CN102745660A (en) * | 2011-04-18 | 2012-10-24 | 中国科学院大连化学物理研究所 | Microfluidic chip based method for synthesizing needle-like hydroxyapatite nanoparticle |
| CN111135883A (en) * | 2019-12-31 | 2020-05-12 | 中山大学 | Ultrahigh-flux platform for screening crystal generation conditions and screening method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101479041A (en) * | 2006-06-28 | 2009-07-08 | 微溶解有限公司 | A device and a method for promoting crystallisation |
| CN102745660A (en) * | 2011-04-18 | 2012-10-24 | 中国科学院大连化学物理研究所 | Microfluidic chip based method for synthesizing needle-like hydroxyapatite nanoparticle |
| CN111135883A (en) * | 2019-12-31 | 2020-05-12 | 中山大学 | Ultrahigh-flux platform for screening crystal generation conditions and screening method |
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