CN114394981B - Multi-tela Wei Nawei flow control continuous crystallization method - Google Patents
Multi-tela Wei Nawei flow control continuous crystallization method Download PDFInfo
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Abstract
The invention discloses a multi-tela Wei Nawei flow control continuous crystallization method, which comprises the following steps: controlling the temperature of a micro-crystallization chip, introducing a sodium-polynitrile liquid medicine with a certain concentration into the micro-crystallization chip at a certain flow rate, enabling the sodium-polynitrile liquid medicine to flow through a micro-channel in the micro-crystallization chip and grow into a nucleus, placing mixed liquid flowing out of the micro-channel into an external container for continuous growth, finally obtaining the sodium-polynitrile medicine, solving the technical problems of discontinuous medicine preparation flow and poor medicine crystal morphology, realizing continuous production of medicine, and having high production efficiency; the prepared medicine has stable quality, narrow distribution range of crystal particle size, relatively consistent crystal form and crystal habit, and is more beneficial to ensuring the quality of downstream medicines; the process is simple to operate and good in repeatability.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy and crystallization, in particular to a flow control continuous crystallization method of polytira Wei Nawei.
Background
Duoteravir (Dolutegravir) is an inhibitor of the reverse transcriptase of the second generation human immunodeficiency virus type 1 (HIV-1) infection, blocking chain transfer of retroviral deoxyribonucleic acid (DNA) integration by binding to the active site of the integrase. Compared with the first generation integrase inhibitors of Raltegravir (Raltegravir) and etiquevir (Elvitegravir), the entecavir has the advantages of low dosage, less side effects, good curative effect, high safety and the like. To improve the bioavailability of the dortefravir in humans, dortefravir is converted into dortefravir sodium (DTG-7).
The prior preparation method of the sodium entecavir (DTG-7) has fewer patents, is prepared in small dosage in a laboratory, and has discontinuous preparation flow of medicines. Therefore, the quality of each batch of medicines prepared by the method is unstable, the grain size distribution of crystals is wide, the crystal forms and the crystal habit are inconsistent, and the quality of the downstream medicines is fluctuated. In addition, the manual operation is complicated, the repeatability is poor, and the medicine effect is influenced by the fact that the chemical bond is required to be destroyed by grinding of the medicine crystal.
The micro-fluidic technology is a technology for carrying out chemical reaction and separation process in a micrometer or millimeter limited space by taking a micro-structural element as a core, and the micro-fluidic technology enhances the mixing and transfer of substances by reducing the dispersion scale of a system, improves the process controllability and efficiency, and integrates and amplifies micro-equipment by taking 'quantity amplification' as a basic rule. The microfluidic continuous crystallization technology combining the microfluidic technology and the continuous crystallization technology has unique advantages, has high mixing efficiency, high heat and mass transfer rate, stable quality of produced medicines, consistent crystal morphology, less investment of equipment funds, and modular design has excellent transportation and potential factors capable of eliminating amplification effects. The technology has low safety, high mixing requirement, high toxicity and strong corrosion, strict material proportion, high pressure and accurate temperature control required reaction and production process, and can be widely applied to actual production as an important means.
Disclosure of Invention
It is an object of the present invention to solve at least the above problems and to provide at least the advantages to be described later.
The invention aims to provide a multi-tela Wei Nawei flow control continuous crystallization method to solve the technical problems of discontinuous drug preparation flow and poor drug crystal morphology.
To achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided a method for fluid controlled continuous crystallization of polytira Wei Nawei, comprising:
controlling the temperature of the micro-crystallization chip, introducing a sodium-polynitrothion liquid medicine with a certain concentration into the micro-crystallization chip at a certain flow rate, enabling the sodium-polynitrothion liquid medicine to flow through a micro-channel in the micro-crystallization chip and grow into a nucleus, placing the mixed solution flowing out of the micro-channel in an external container for continuous growth, and finally obtaining the sodium-polynitrothion medicine.
Preferably, the micro-crystallization chip is maintained at 50-80 ℃ through a constant temperature control groove; the structure of the micro-crystallization chip comprises:
a first S-shaped channel;
a first Y-shaped channel; and
a second S-shaped channel;
wherein, the first Y-shaped channel, the first S-shaped channel and the second S-shaped channel form a T-shaped structure at the convergence part, and the outlet of the first S-shaped channel and the inlet of the second S-shaped channel are on the same straight line;
the first S-shaped channel has a channel width of 600 μm, the first Y-shaped channel has a channel width of 500 μm, and the second S-shaped channel has a channel width of 600 μm.
Preferably, the entecavir is dissolved in isopropanol with an initial concentration of the entecavir in isopropanol between 3.5mg/ml and 6.5mg/ml, and the entecavir solution is pumped through a syringe pump into the inlet of the first S-channel at a flow rate of between 0.05ml/min and 0.1 ml/min.
Preferably, sodium hydroxide solution enters the first inlet of the first Y-shaped channel through a syringe pump at a flow rate of 0.01 ml/min-0.03 ml/min, and the initial concentration of sodium hydroxide is 18 mg/ml-21 mg/ml;
nitrogen enters the second inlet of the first Y-shaped channel at a flow rate of 0.3 ml/ml-1.3 ml/min through the regulation and control of the gas flowmeter.
Preferably, sodium hydroxide solution and nitrogen form gas-liquid slugging through a Y-shaped mixed structure in a first Y-shaped channel, at a T-shaped structure, the dortebuvir solution is mixed with the gas-liquid slugging to react and nucleate, the liquid medicine enters a second S-shaped channel along with gas-liquid fluid and finally is taken out of a chip, the liquid medicine enters a beaker, the crystal nucleus continues to grow up in the beaker to form crystal slurry, and the dortebuvir sodium medicine is obtained through centrifugation, washing, ultrasonic treatment and decompression drying.
Preferably, the micro-crystallization chip is controlled at 66.1 ℃, the initial concentration of the entecavir in isopropanol is 5.0mg/ml, the initial concentration of sodium hydroxide is 19.7mg/ml, the entecavir solution and the sodium hydroxide solution respectively enter the chip through a syringe pump at the flow rates of 0.075ml/min and 0.02ml/min, and the nitrogen enters the chip through a gas flowmeter in a regulating and controlling way of 0.95 ml/min.
Preferably, the micro-crystallization chip is maintained at 15-35 ℃ through a constant temperature control groove, and the structure of the micro-crystallization chip comprises a second Y-shaped channel and a third S-shaped channel, wherein the flow path width of the second Y-shaped channel and the third S-shaped channel is 800 μm.
Preferably, the sodium entecavir liquid medicine enters the first inlet of the second Y-shaped channel through a syringe pump at the flow rate of 0.1 ml/min-0.3 ml/min, and the initial concentration of the sodium entecavir liquid medicine is 8 mg/ml-12 mg/ml; isopropyl alcohol is introduced into the second inlet of the second Y-shaped channel through a syringe pump at a flow rate of 0.1ml/min to 0.3 ml/min.
Preferably, the sodium entecavir liquid medicine and the isopropanol are premixed in the chip through a Y-shaped mixing structure, enter a third S-shaped channel and nucleate in the third S-shaped channel; after flowing out of the micro-crystallization chip, the mixed solution enters a kettle-type crystallizer to continue growing for a period of time; the slurry obtained in the kettle-type crystallizer is filtered, washed, subjected to ultrasonic treatment and dried under reduced pressure to obtain the sodium entecavir micropowder.
Preferably, the microcrystalline chip is maintained at a temperature between 25 ℃ through a constant temperature control groove, the sodium entecavir liquid medicine and the isopropanol are respectively injected into the chip through a syringe pump at a flow rate of 0.2ml/min and a flow rate of 0.2ml/min, and the initial concentration of the sodium entecavir liquid medicine is 10mg/ml.
The invention at least comprises the following beneficial effects:
1. the process realizes continuous production of the medicine and has high production efficiency;
2. the preparation method has stable medicine quality, narrow crystal particle size distribution range, relatively consistent crystal form and crystal habit, and is more beneficial to ensuring the downstream medicine quality;
3. the method is simple in process operation and good in repeatability.
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 an X-ray powder diffraction pattern of a first embodiment of a medicament;
FIG. 2 is an X-ray powder diffraction pattern of a second embodiment of the medicament;
FIG. 3 is a diagram showing the structure of a microchip according to the first embodiment;
FIG. 4 is a diagram showing the structure of a microchip according to the second embodiment;
fig. 5 is a morphology diagram of a crystal morphology diagram of sodium adefovir with a supersaturation degree of 2.4;
FIG. 6 is a morphology diagram of a crystal morphology diagram of sodium entecavir with a supersaturation degree of 1.85;
FIG. 7 is a graph of the morphology of sodium entecavir crystals with an antisolvent fraction of 50%;
fig. 8 is a graph of the morphology of sodium entecavir crystals with an antisolvent fraction of 70%.
Detailed Description
The present invention is described in further detail below with reference to the drawings to enable those skilled in the art to practice the invention by referring to the description.
It will be understood that terms, such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
Example 1
The invention provides a continuous reaction crystallization production method based on a microfluidic technology, which aims at the defects of complicated operation, non-uniform crystal quality, needle-like crystal morphology and high solvent consumption of the existing kettle type intermittent production process of sodium entecavir (DTG-7).
The invention develops a production method of multi-tela Wei Nawei fluid control continuous heterogeneous reaction crystallization, nitrogen is introduced into a micro-crystallization chip, and the preparation of the micro-crystallization chip is detailed in the prior application patent of the applicant: a portable chip thermocompression bonding device performs mixing and reaction of sodium hydroxide and polyttira Wei Yaoye in the micro-crystallization chip, and further nucleates medicine crystals in the micro-channel. Continuous heterogeneous reaction crystallization is realized by further growing the sodium entecavir crystal outside the micro-channel.
In the mode, the introduction of the gas phase enhances the liquid medicine mixing effect in the micro-channel, rapidly brings out crystal nucleus, and avoids the problem of channel blockage caused by continuous crystallization. The implementation of the process is to design a high-flux microfluidic clamp capable of placing a micro-crystallized glass chip, and the details are shown in the prior application patent of the applicant: the temperature-control pressure-resistant clamp device of the high-flux visual micro-fluidic chip is beneficial to the entry and the outflow of liquid medicine and realizes the effect of temperature control.
In order to ensure accurate liquid inlet amount and liquid medicine proportion, a syringe pump is adopted to push liquid medicine and a gas flowmeter to control nitrogen flow. The micro-crystallization chip is made of glass material and is prepared by wet etching and hot-press bonding. The internal structure of the chip consists of Y-shaped mixing, T-shaped mixing and downstream mixing channels. And maintaining the temperature of the chip at 66.1 ℃, and enabling sodium hydroxide solution and nitrogen to pass through the Y-shaped channel to form gas-liquid slug flow. At the second T-shaped structure, the solution of the entecavir containing isopropanol is mixed with the gas-liquid slug flow, the entecavir reacts with sodium hydroxide rapidly, and the gas-liquid slug flow is formed by nitrogen to be taken away rapidly. After passing through the S-shaped channel, the liquid medicine and the gas flow through the pipeline and enter the beaker after exiting from the outlet of the chip. The sodium crystal of the dortefravir is grown in a beaker, and the dortefravir Wei Najing slurry is obtained after a period of time. After centrifugation of the slurry several times, it was dispersed in isopropanol and the sample sonicated for 20min. And then the sample is dried under reduced pressure to obtain the sodium entecavir micropowder. The reaction equation for the polytira Wei Cheng salt is as follows:
specifically, the invention provides a production method of a multi-tela Wei Nawei fluid control heterogeneous continuous reaction crystal, which is characterized in that nitrogen is introduced into a micro-crystallization chip, heterogeneous flow is formed in the micro-crystallization chip to enhance the reaction mixing strength, crystal nucleus is formed, and continuous heterogeneous reaction crystallization is realized in a mode of further growing outside a micro-channel, so that a multi-tela sodium crystal is obtained. In the present invention, the chip temperature was maintained at 66.1 ℃ by a thermostatic temperature-controlled bath. The initial concentration of the dortefravir in isopropanol is 5.0mg/ml, and the initial concentration of the sodium hydroxide is 19.7mg/ml. The dortefravir solution and the sodium hydroxide solution are respectively fed into the chip through injection pumps at flow rates of 0.075ml/min and 0.02 ml/min. Nitrogen enters the chip by regulating and controlling the flow rate of the nitrogen to be 0.95ml/min through a gas flowmeter. The flow path width in the sodium hydroxide and nitrogen micro-channels is 500 mu m, the flow path micro-channel width of the entecavir solution is 600 mu m, and the mixing section channel width is 600 mu m. Sodium hydroxide solution is injected into the chip through a channel 1 of the micro-crystallization chip 1 shown in fig. 3, a channel 2 of the nitrogen channel micro-channel chip is injected into the chip, two fluids form gas-liquid slugging through a Y-shaped mixed structure on the chip, and at the T-shaped structure, the Polytevavir solution is mixed with the gas-liquid slugging to react and nucleate. Then the liquid medicine enters the S-shaped channel along with the gas-liquid fluid, and finally is carried out of the chip and enters the beaker. And (3) continuously growing crystal nucleus in the beaker to form crystal slurry, and obtaining the sodium entecavir medicament through centrifugation, washing, ultrasonic treatment and decompression drying.
The invention is a reaction and crystallization one-step method of microfluidic continuous drugs, reduces operation steps, and solves the problem of microchannel blockage caused by continuous crystallization. Compared with the crystals obtained by the existing intermittent production, the crystal powder obtained by the technical route has the advantages that the grain size distribution of the crystals is narrowed, the morphology of the crystals is changed from needle shape to rod shape, the availability of the human body to the medicine is improved, and the subsequent medicine compression molding is easy. The X-ray powder diffraction diagram of the crystal form prepared by the production method is shown in figure 1. It has characteristic diffraction peaks at 6.4 ° ± 0.2 °,9.2 ° ± 0.2 °,13.8 ° ± 0.2 °,14.6 ° ± 0.2 °, 6.4 ° ± 0.2 °,17.6 ° ± 0.2 °,19.2 ° ± 0.2 °,21.8 ° ± 0.2 °,24.1 ° ± 0.2 °,26.4 ° ± 0.2 °,28.7 ° ± 0.2 ° in the X-ray diffraction pattern. After the comparison of the existing multi-tela Wei Najing type patent is searched, the diffraction peak data of the crystal is obtained through experiments, and the medicine crystal produced by the embodiment is consistent with the existing medicine crystal in the market. Further illustrates that the crystal of the sodium entecavir obtained by the production method has a fixed crystal form.
The supersaturation degree of the reactive crystal of the first embodiment is tested between 1.2 and 2.4, and a plurality of test researches prove that when the supersaturation degree is 2.4, the sodium entecavir crystal is agglomerated, as shown in figure 5. When supersaturation is 1.85, the crystal dispersibility of the sodium entecavir is good, and the crystal aspect ratio is moderate, as shown in fig. 6. The optimal drug therefore has a saturation of 1.85, i.e. the specific material flow ratio and concentration described in example one.
For the structure and application of the microchip, please see the applicant's prior application: the invention discloses a continuous crystallization micro-nano chemical chip and application thereof, which are improvements and specific applications in the technology. The invention introduces nitrogen into the micro-channel to form gas-liquid phase mixture, which has higher mixing effect than the liquid-liquid phase mixture formed by introducing paraffin. The liquid medicine is easier to form uniform mixing in the adjacent nitrogen slug spaces, thereby shortening the reaction time of the medicine. In addition, the nucleated crystals can be quickly taken away by the high nitrogen flow, so that the crystals are prevented from growing in the micro-channels and blocking the channels. In addition, after the nitrogen is wrapped with the liquid medicine crystal slurry and flows out from the chip, the step of separating the nitrogen from the liquid medicine slurry does not exist due to the self-dissipation property of the gas. However, the mixture of paraffin and liquid crystal slurry also needs subsequent separation.
In this embodiment, the microfluidic heterogeneous continuous reaction crystallization method of the sodium entecavir comprises: controlling the temperature of a micro-crystallization chip, forming a slug flow of nitrogen with a certain flow rate and a sodium hydroxide solution with a certain concentration in a micro-channel of the chip, and then enabling a polyntebuvir solution with a certain concentration to enter a mixed crystal of the micro-crystallization chip at a certain flow rate so as to enable the polyntebuvir to react with sodium hydroxide to obtain the target medicine, namely the sodium polyntebuvir. The sodium entecavir medicine liquid flows through the micro-channel inside the micro-crystallization chip and grows to form nucleus, and the crystal slurry of the medicine liquid flowing out of the micro-channel is placed in an external container to continue growing, so that the sodium entecavir medicine is finally obtained.
Example two
The invention provides a production method of a multi-tela Wei Nawei fluid control homogeneous continuous anti-solvent crystal, which combines a micro-crystallization chip and a kettle-type crystallizer, and adopts a mode of mixing and nucleating inside the micro-crystallization chip and further growing outside a micro-channel (inside the kettle-type crystallizer) to realize continuous anti-solvent crystallization so as to obtain a multi-tela sodium crystal. In this way, excessive growth of crystals in the micro-channels is avoided, thereby causing pipeline blockage. The micro-crystallization chip is made of glass material and is prepared by wet etching and hot-press bonding. The microcrystalline chip consisted of a Y-type hybrid and an S-coil through which sodium entecavir/dimethyl sulfoxide (drug/solvent) and isopropyl alcohol (anti-solvent) were premixed and then continued to flow along the S-coil with a length of 0.2m and nucleate in the coil. The kettle-type crystallizer is formed by combining a beaker and a stirring magnet, and after the mixed solution flows out of a micro-crystallization chip, the mixed solution continuously grows for a period of time in the kettle-type crystallizer. The slurry obtained in the kettle-type crystallizer is filtered, washed, dispersed in isopropanol again, and the sample is subjected to ultrasonic treatment for 20min. The purpose of ultrasound is to reduce the aggregation between crystals. And drying the sample to obtain the sodium entecavir micropowder.
Specifically, in the present invention, the experimental temperature was controlled at 25℃by a thermostatic bath. The initial concentration of the sodium entecavir liquid medicine is 10mg/ml. The sodium entecavir liquid medicine and the isopropanol are respectively injected into the chip through a syringe pump at the flow rates of 0.2ml/min and 0.2 ml/min. All channels of the microchip were 800 μm wide. The sodium entecavir liquid medicine is injected into the chip through the channel 2 of the micro-crystallization chip 2 shown in fig. 4, the isopropyl alcohol is injected into the chip through the channel 3 of the micro-crystallization chip, the two are premixed in the chip through the Y-shaped mixing structure 4, then the sodium entecavir liquid medicine continues to flow along the S-shaped coil 5 with the length of 0.2m, and the isopropyl alcohol is nucleated in the coil. And after flowing out of the micro-crystallization chip, the mixed solution enters the kettle-type crystallizer 6 to continue growing for a period of time. And filtering, washing, ultrasonic treatment and drying under reduced pressure the slurry obtained in the kettle-type crystallizer to obtain the sodium entecavir micropowder.
The invention reduces the adhesion of crystals on the wall surface of the micro-channel and realizes continuous crystallization. As a result, it was revealed that the crystal grain diameter D90 of the crystal powder obtained by the production method of the present invention was reduced from 32 μm to 9.7. Mu.m, as compared with the crystal powder obtained by the conventional batch production method. The X-ray powder diffraction diagram of the crystal form prepared by the production method is shown in figure 2. It has characteristic diffraction peaks at 6.4 ° ± 0.2 °,9.2 ° ± 0.2 °,13.8 ° ± 0.2 °,14.6 ° ± 0.2 °, 6.4 ° ± 0.2 °,17.6 ° ± 0.2 °,19.2 ° ± 0.2 °,21.8 ° ± 0.2 °,24.1 ° ± 0.2 °,26.4 ° ± 0.2 °,28.7 ° ± 0.2 ° in the X-ray diffraction pattern. After the comparison of the existing multi-tela Wei Najing type patent is searched, the diffraction peak data of the crystal is obtained through experiments, and the medicine crystal produced by the embodiment is consistent with the existing medicine crystal in the market. Further illustrates that the crystal of the sodium entecavir obtained by the production method has a fixed crystal form.
The anti-solvent ratio of the second embodiment is tested in the range of 50-90%, and when the anti-solvent ratio is in the range of 50-66%, the prepared sodium entecavir crystal has good dispersibility, and the crystal morphology is in a block shape as shown in figure 7. At an anti-solvent ratio of 70-90%, the sodium crystal of the entecavir is severely agglomerated, as shown in fig. 8. Therefore, the optimal proportion of the anti-solvent is selected in the range of 50-66%, namely the flow ratio of the sodium entecavir liquid medicine to the isopropanol in the second embodiment.
In this example, the homogeneous continuous anti-solvent crystallization method of sodium entecavir comprises: controlling the temperature of the micro-crystallization chip, introducing a sodium-polynitrothion liquid medicine with a certain concentration into the micro-crystallization chip at a certain flow rate, enabling the sodium-polynitrothion liquid medicine to flow through a micro-channel in the micro-crystallization chip and grow into a nucleus, placing the mixed solution flowing out of the micro-channel in an external container for continuous growth, and finally obtaining the sodium-polynitrothion medicine.
The existing mode for preparing the sodium entecavir at present is a batch kettle reaction crystallization mode, and compared with the patent: the crystal form of the sodium entecavir and the preparation method CN 112225749A thereof, the reaction time is 3-5 hours, and the obtained crystal is needle-shaped and slender crystal. The crystal aspect ratio is too large, the bioavailability of the medicine is possibly low, and the crystals are easy to break when the subsequent medicine is pressed. In the two ways of microfluidic continuous crystallization, the sodium entecavir in the reaction crystallization mode is a rod-shaped crystal, and the sodium entecavir in the anti-solvent crystallization mode is a block-shaped crystal.
Compared with the prior art, the preparation method solves the technical problems of discontinuous drug preparation flow and poor drug crystal morphology, realizes continuous production of drugs, and has high production efficiency; the prepared medicine has stable quality, narrow distribution range of crystal particle size, relatively consistent crystal form and crystal habit, and is more beneficial to ensuring the quality of downstream medicines; the process is simple to operate and good in repeatability.
Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown and described, it is well suited to various fields of use for which the invention would be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the specific details and illustrations shown and described herein, without departing from the general concepts defined in the claims and their equivalents.
Claims (2)
1. A method for continuously crystallizing polytira Wei Nawei in a fluid control manner, which is characterized by comprising the following steps:
controlling the temperature of a micro-crystallization chip, introducing a sodium-polynitrile liquid medicine with a certain concentration into the micro-crystallization chip at a certain flow rate, enabling the sodium-polynitrile liquid medicine to flow through a micro-channel in the micro-crystallization chip and grow into a nucleus, placing the mixed solution flowing out of the micro-channel in an external container for continuous growth, and finally obtaining the sodium-polynitrile medicine;
the micro-crystallization chip is maintained at 50-80 ℃ through a constant temperature control groove; the structure of the micro-crystallization chip comprises: a first S-shaped channel; a first Y-shaped channel; a second S-shaped channel; wherein, the first Y-shaped channel, the first S-shaped channel and the second S-shaped channel form a T-shaped structure at the convergence part, and the outlet of the first S-shaped channel and the inlet of the second S-shaped channel are on the same straight line; the flow path width of the first S-shaped channel is 600 mu m, the flow path width of the first Y-shaped channel is 500 mu m, and the flow path width of the second S-shaped channel is 600 mu m;
feeding sodium hydroxide solution into a first inlet of a first Y-shaped channel through a syringe pump at a flow rate of 0.01-0.03 ml/min, wherein the initial concentration of sodium hydroxide is 18-21 mg/ml; nitrogen enters a second inlet of the first Y-shaped channel at a flow rate of 0.3ml/min-1.3ml/min through gas flowmeter regulation and control;
dissolving the dortefravir in isopropanol, wherein the initial concentration of the dortefravir in the isopropanol is between 3.5mg/ml and 6.5mg/ml, and enabling the dortefravir solution to enter the inlet of the first S-shaped channel through a syringe pump at a flow rate of 0.05ml/min to 0.1 ml/min; and the sodium hydroxide solution and nitrogen form gas-liquid slugging through a Y-shaped mixed structure in a first Y-shaped channel, the dortebuvir solution is mixed with the gas-liquid slugging in a T-shaped structure to react and nucleate, the liquid medicine enters a second S-shaped channel along with gas-liquid fluid and finally is taken out of a chip, the liquid medicine enters a beaker, crystal nuclei continue to grow up in the beaker to form crystal slurry, and the crystal slurry is subjected to centrifugation, washing, ultrasonic treatment and decompression drying to obtain the dortebuvir sodium medicine.
2. The method for continuous crystallization of the dorame Wei Nawei flow control according to claim 1, wherein the micro-crystallization chip is controlled at 66.1 ℃, the initial concentration of the dorame in the isopropanol is 5.0mg/ml, the initial concentration of the sodium hydroxide is 19.7mg/ml, the dorame solution and the sodium hydroxide solution are respectively fed into the chip through a syringe pump at the flow rates of 0.075ml/min and 0.02ml/min, and the nitrogen gas is controlled to be 0.95ml/min through a gas flowmeter.
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| CN111701631A (en) * | 2020-06-28 | 2020-09-25 | 华东理工大学 | Temperature-control pressure-resistant clamp device of high-flux visual micro-fluidic chip |
| CN113332744B (en) * | 2021-05-27 | 2023-01-03 | 华东理工大学 | Continuous crystallization micro-nano chemical chip and application thereof |
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