WO2016062241A1

WO2016062241A1 - Dynamically-monitoring high-frequency ultrasonic atomizing micro-granule preparation system

Info

Publication number: WO2016062241A1
Application number: PCT/CN2015/092322
Authority: WO
Inventors: 甘勇; 张馨欣; 朱全垒; 夏登宁; 俞淼荣; 朱春柳
Original assignee: 中国科学院上海药物研究所
Priority date: 2014-10-21
Filing date: 2015-10-20
Publication date: 2016-04-28
Also published as: CN105582683B; CN105582683A

Abstract

A dynamically-monitoring high-frequency ultrasonic nanometer atomizing granule preparation system, mainly consisting of a high-frequency ultrasonic nanometer atomizing device, a real-time multipoint dynamic nanoparticle size and state monitoring device (49, 50), an efficient laminar flow static electricity collecting device, an inert gas circulating and organic solvent recycling device, and a software automation control and data integration processing module (51); the system realizes a nanometer-scale preparation of a micro-sample, introduces real-time dynamic monitoring device, and timely monitors the effect of each parameter on the quality of nanoparticle via a data integration module or a software.

Description

Dynamically monitored high frequency ultrasonic atomized particle preparation system

Technical field

The invention relates to the field of nanoparticle preparation and collection devices, in particular to a dynamic monitoring high frequency ultrasonic atomized particle preparation system, and more particularly, the system can monitor the particle size, particle shape and other parameters of the nanoparticles in real time. Further process optimization provides guidance. The system is suitable for the preparation of nanoparticles for a small amount of samples, and has the advantage of high yield.

Background technique

As an important new delivery system, nanotechnology has brought tremendous changes and developments in the fields of biomedicine, biotechnology and biomaterials, and has become a hot research direction in recent years.

However, existing nanocarrier preparation techniques and equipment still have many problems in practical application:

(1) Insufficient preparation for micro-samples: In the early stages of development, candidate compounds, biomaterials, or biotech products are rarely obtained (in milligrams) and are very valuable. Researchers hope to complete them with as few samples as possible. Evaluation of drug-forming properties and activity in vitro and in vivo. However, the minimum preparation amount of the existing nanocarrier preparation equipment such as a jet mill, a ball mill, a colloid mill, a high pressure homogenizer, etc. often requires several grams or even several tens of grams of raw materials, and the preparation process requires multiple steps, including pulverization, Emulsification, drying, etc., the preparation process is cumbersome and complicated, and the yield is extremely low (gram-level sample, the yield is often less than 50%). This has greatly limited the development of innovative products.

(2) It can not meet the needs of rapid preparation and stable preservation of nano-samples: common nano-carriers such as liposome, nano-crystal, nano-particle, etc. are mostly dispersed and prepared in a solution environment by the principles of homogenization, pulverization and polymerization. Due to the huge surface energy of the nanoparticles, they are thermodynamically unstable in the dispersed state in the solution. During the placement process, particles collide with each other, the particle size increases, and the drug is leaked. At the same time, some drugs or compounds are unstable. It is easily hydrolyzed or oxidized during the placement process; thus seriously affecting the effectiveness and safety. Therefore, it is necessary to further dry the prepared nanocarrier. At present, the drying technology (freeze drying) commonly used has many problems: low efficiency, long cycle, improper formulation (such as protective agent, solvent, buffer, etc.) or process selection, which may lead to aggregation of nanocarriers, hydrolysis of drugs, etc., and cannot be quickly prepared and Stable preservation of nano samples.

(3) It is unable to meet the needs of nanometer sample detection and preparation integration: the particle size and particle shape of nanoparticles are important factors affecting their distribution in the body, target organ enrichment rate, drug efficacy and safety. The existing nano-preparation equipment cannot monitor and control the size and shape of the particles on-line, and often requires repeated tests to determine the parameters of the process before formal sample preparation can be performed. This not only fails to meet the needs of micro-sample preparation in the early stage of the research, but also has hidden dangers of uneven quality due to environmental changes in the mass production process.

(4) The requirements for green preparation of nano-samples cannot be met: a large number of candidate drugs or new compounds need to be dissolved by special organic solvents for subsequent treatment due to poor water solubility. The existing equipment lacks an organic solvent recovery system, and it is difficult for organic solvents to completely circulate. It is recycled and discharged into the air, causing pollution. In addition, the collection efficiency of particles after drying is limited. For example, in the spray drying technology, the conventional cyclone separation collection system has low collection efficiency (usually less than 30%) for particles with a particle size below 10 microns, and the micro particles are easy. Floating in the air, and these particles may be very toxic (such as anti-cancer drug particles), which may cause potential harm to the operator and the surrounding environment, which is difficult to meet the needs of the laboratory green preparation.

Therefore, in order to meet the needs of the preparation of innovative nanocarriers, it is urgent to develop an apparatus with on-line monitoring and control functions capable of preparing nanocarriers with good stability in a small, rapid and efficient manner.

At present, the preparation of nanocarriers in domestic and foreign research is mostly carried out by nano-drying two-step process, that is, firstly, high-pressure homogenization, colloid milling, polymer polymerization and other methods are used to prepare nanocarriers in a solution system, and then freeze-drying and the like. The nanocarriers are prepared as a solid powder that is stable for long-term storage.

However, these commonly used nanocarrier preparation techniques require multi-step operation on the one hand, the preparation process is cumbersome and complicated, and the parameters are difficult to control; common drying techniques (freeze drying) have many problems: long cycle, ingredients (such as protective agent, solvent, buffer) Etc.) or improper process selection can easily lead to unstable aggregation of nanocarriers, drug hydrolysis, etc., requiring targeted trial and error. The use of existing techniques for the preparation of nanocarriers requires at least a few grams to a few tens of grams of starting material, which is almost impossible to achieve for micro-synthesized compounds, which greatly limits the development and high-throughput evaluation of innovative products.

Spray drying techniques are available for the preparation of nanocarriers, polypeptide proteins, and nanoemulsion dry powders. During the spray drying process, the material is atomized into micron-sized droplets. The evaporation and drying surface area is very large, and the processed materials can be heated and dried instantaneously, and the drying efficiency is much greater than that of freeze-drying. The powder after spray drying can be re-dispersed by adding an aqueous solution. Relative to freeze drying, spray drying is a drying technology that can realize one-step preparation of microcarriers, which is beneficial to mass production. However, there are still some shortcomings in current spray drying equipment:

At present, the particle size of the products prepared by spray drying is mostly on the order of micrometers, the particle size distribution is wide, and it is uncontrollable, and the micron-sized particles can no longer meet the clinical needs. At present, the new atomizing device introduced by BUCHI of Switzerland is manufactured according to the principle of piezoelectric driven reciprocating film vibration. The film having a pore diameter of 4-7 um vibrates at a fixed frequency of 60 kHz to atomize the droplets. However, due to its narrow aperture, it is easily blocked by materials, and once the nozzle is blocked, the nozzle must be replaced. The solution must be filtered through a microporous membrane to be sprayed and therefore cannot be used for post treatment of the nanosuspension. In addition, the natural frequency of 60 kHz used does not meet the atomization needs of viscous materials.

The traditional spray drying technology collects dry powder particles by the principle of cyclone separation. The smaller particle size will fly with the airflow and will not deposit at the collection port, resulting in a low yield of up to 50%. For nanoparticles Collected, the yield is even lower, or not collected at all. Therefore, the traditional spray drying technology requires at least tens of grams of drugs per experiment, which is difficult to achieve in the early stage of new drug development.

For nanoformulations, the particle size distribution and morphology of the particles are very critical parameters. After the nano-formulation is administered, the particle size not only affects the dissolution of the drug, but also affects the distribution in the body and ultimately leads to a difference in clinical therapeutic effects. In order to obtain the ideal preparation and maximize the efficacy of the active ingredient, it is often necessary to carry out multiple experiments, constantly adjust the prescription, optimize the preparation, and repeatedly perform instrument disassembly to obtain samples for particle size and shape detection, which is not only time-consuming but more important. It is a lot of active ingredients.

Conventional spray drying equipment mostly uses an open drying system, which has certain limitations for the prepared product and solvent system. Spray drying containing organic solvents (flammable and explosive gases) and oxidizable substances can cause the product to react with oxygen in hot air or even cause an explosion during the passage of hot air. In addition, some products are highly toxic. If an open drying system is used, the exhaust gas required to be discharged must be cleaned, but the highly toxic substances in the exhaust gas cannot be completely removed by cyclone dust removal or bag dust removal.

Summary of the invention

The invention aims at the special requirements of nanometerization, micronization and visual controllability in the development of innovative drugs, and develops a high-frequency ultrasonic spray drying device with real-time monitoring function, and expands the spray drying technology in the field of nanoparticle preparation. application. The object of the present invention is to adopt a high-frequency ultrasonic spray and electrostatic collection technology, combined with the concept of dynamically measuring the particle size distribution and morphology of nanoparticles, and design a high-frequency ultrasonic nano-atomized particle preparation system with dynamic monitoring function. The preparation system is implemented Nanocrystallization, micronization, and visual controllability of particle preparation.

According to the present invention, a high frequency ultrasonic nano atomized particle preparation system with dynamic monitoring function is provided, characterized in that the system comprises: a high frequency ultrasonic nano atomizing device; a multi-point dynamic nano particle real-time particle size and shape monitoring device Laminar electrostatic collection system; inert gas circulation and organic solvent recovery system; and automated control and data integration processing device, wherein the liquid (solution, suspension or colloidal solution) is atomized to nanometer by high frequency ultrasonic nano atomizing device Stage droplets; dried into solid particles by laminar drying gas blowing in a laminar electrostatic collection system, and collected solid particles in an electrostatic collector of an efficient laminar electrostatic collection system; drying gas is circulated through inert gas and organic After the solvent recovery system, the organic solvent is removed to realize the recycling of the inert gas; wherein the multi-point dynamic nanoparticle real-time particle size and shape monitoring device collects and calculates relevant parameters of the dried solid particles and obtains data and Parameters are sent to the automated control and data integration processing device by the automation System integration and data processing means associated database solid particles through the input parameters and parameter data a plurality of times, a final model is a neural network control.

Advantageously, said high frequency ultrasonic nano atomizing device comprises a high precision positive displacement syringe pump, a flow rate regulator, an ultrasonic vibration nozzle and a control unit; said control unit being electrically coupled to said ultrasonic vibration nozzle to provide an electrical signal thereto The syringe pump is connected to the ultrasonic vibration nozzle through a pipeline to supply liquid thereto, and the flow rate regulator is connected to the syringe pump.

Advantageously, the ultrasonic vibration nozzle comprises a housing, a transducer, a metal tube, a spout, a holder, an active electrode and a ground electrode; wherein the nozzle is conical, the surface of which is formed to maximize atomization of the liquid; The control unit in the high-frequency ultrasonic nano-atomization device has a variable frequency power supply, which can be used to apply a varying frequency to the transducer of the ultrasonic vibration nozzle to vibrate, and the vibration is transmitted to be closely mounted thereto. On the metal tube of the ultrasonic vibration nozzle together, the metal tube vibrates together with the frequency of the transducer and amplifies the vibration frequency; the liquid to be treated (solution, suspension or colloidal solution) is a high-precision positive displacement syringe pump Delivered to the spout of the ultrasonic vibrating nozzle, the vibration frequency overcomes the surface tension of the liquid, thereby forming minute droplets, and nano atomizing the liquid sample, and the solvent in the mist is heated in a dry gas heated by the heater to a certain temperature ( The gas is selected from the group consisting of nitrogen, helium, carbon dioxide, and mixtures thereof to evaporate instantaneously to form dry solid particles. This design can meet the needs of stable preparation of particles of different sizes. At the same time, since the atomizer frequency can be changed, it can be adapted to the atomization of different viscous samples.

The transducer can be any type of piezoelectric crystal, such as piezoelectric ceramics, quartz, or the like. The liquid is fed into the ultrasonic vibration nozzle through a stable high-precision positive displacement syringe pump, and the liquid is ultrasonically vibrated. The surface of the atomizing surface of the metal tube of the nozzle is subjected to high frequency vibration to form minute droplets to sufficiently atomize the material. This can meet the needs of different viscosity samples and nanoparticle size. In addition, the high-precision positive displacement syringe pump used for liquid delivery adjusts the flow rate to adjust the atomization droplet uniformity.

An efficient laminar flow electrostatic collection system according to the present invention, comprising a cavity, a drying chamber, a laminar flow generating member, and an electrostatic collector, wherein the laminar flow generating member is composed of a porous metal foam plate, and the electrostatic collector is collected by a corona effect Powder particles suspended in a gas. The nano-droplets are carried by a drying gas (selected from nitrogen, helium, carbon dioxide, and a mixture thereof) through the drying chamber and into the electrostatic collector. The laminar gas of this high efficiency laminar flow electrostatic collection system is produced from a porous metal foam sheet. The porous metal foam board is composed of a metal skeleton and pores, and has a large number of pores inside. When a high velocity gas (ie, a gas flowing in the system) strikes the porous metal foam plate, the gas enters the pore passage of the porous metal foam plate, thereby reducing the gas flow rate, and finally forming a laminar flow instead of a turbulent flow, preventing the dry particles from adhering. In the case of the inner wall of the drying chamber.

The inert gas and organic solvent recovery system according to the present invention comprises a first filter, a heat exchanger, a condenser (which may preferably be a low temperature coil condenser, a plate heat exchanger or a tube plate heat exchanger, etc.), Liquid collection bottle, oxygen content sensor, safety relief valve and second filter. When a gas containing a gaseous organic solvent (for example, ethanol, dichloromethane, chloroform) passes through a condenser, it is cooled to a temperature below the boiling point of the organic solvent with chilled water, and the organic solvent is condensed into a liquid, and after passing through the condenser, the organic solvent Separate into the reservoir collection bottle. Then, the separated gas is purified by a second filter (activated carbon adsorption filter) and returned to the drying chamber, wherein the second filter uses a porous solid adsorbent for adsorption-desorption to separate the inert gas. At the same time, the operation of the gas in the closed loop of the inert gas circulation and organic solvent recovery system is operated under an inert gas atmosphere to prevent the production of any explosive mixture.

The multi-point dynamic nanoparticle real-time particle size and shape monitoring device according to the present invention monitors the particle size and roundness of the dried particles dried by the dry gas formed by spraying, and collects relevant parameters of the particles in time. Calculation. The monitoring device can obtain the information data related to the product quality in the preparation process in time, which is beneficial to quickly realize the optimization of the preparation parameters, avoid repeated labor and waste valuable raw materials. Specifically, the multi-point dynamic nanoparticle real-time particle size and shape monitoring device of the present invention monitors particle size and distribution by using light diffraction or scattering techniques (such as laser diffraction), and combines dynamic image analysis on particles. Morphology is monitored. By comprehensively analyzing the particle size and roundness data of the dried particles obtained by the on-line monitoring device, an indication of adjusting the sample delivery parameters, the ultrasonic vibration nozzle parameters, or the dry gas parameters is obtained. Further combined with an automated control software device, Through the input of multiple data and parameters, the association database of granularity, granular shape and control parameters is established, and finally the neural network control model is established to realize the rapid feedback of analyzing product quality information and adjusting specific control parameters.

The software automatic control and data integration processing device according to the present invention controls parameters such as ultrasonic atomization power and frequency, injection pump flow rate, heating temperature control, inert gas circulation flow rate and pressure, and electrostatic generator voltage through a serial port. Communication, TCP/IP communication, etc., realize precise control according to the control model; realize high-speed data transmission and storage through the combination of optical communication and internal high-speed bus; design and implement related algorithms by analyzing the theory and algorithm of related data processing According to the standard of dynamic image analysis, the algorithm of dynamic image processing is designed and implemented; the data of the particle size and morphology of the dried nanoparticles are integrated and analyzed; finally, the influence of each parameter on the quality of the nanoparticles is obtained, and the statistical results and trend prediction are formed. An intuitive image/chart display. Software functions include control functions, device management functions, data transmission and storage functions, data processing functions, statistical analysis functions and other modules, running in the PC environment, support WINDOWS 7, Windows XP and other operating systems; support mobile terminal test results push function.

The features of the invention are as follows:

(1) A one-step rapid preparation of a trace nanocarrier is realized, and the preparation efficiency is improved. The high-frequency ultrasonic nano atomizing device developed by the invention atomizes the drug solution into an aerosol of 200-1000 nm through an ultrasonic atomizer with a vibration frequency of up to 200 KHz, and instantaneously dries into nano-sized powder particles under laminar gas heating conditions; Subsequently, the high-efficiency laminar flow electrostatic collecting device collects the microparticles by the principle of electrostatic adsorption, and can rapidly prepare the nanocarrier sample in one step. Since the high-frequency ultrasonic nozzle has no dead volume during the spraying process, the yield is as high as 90% or more, and the nano-formulation can be lost in the whole preparation process, so it can be used for the preparation of the milligram-scale nanocarrier.

(2) Based on the QbD (Quality by Design) concept, a dynamic online monitoring device is introduced in the spray drying equipment. The device can perform on-line full-scale monitoring of the particle size and morphology of the product in the main moving route of the nanoparticle in the preparation system, and simultaneously adopts a data integration processing module for simultaneous ultrasonic atomization and parameter and dry nanoparticle size and morphology. The data is integrated and analyzed, and finally the influence of each parameter on the quality of the nanoparticles is obtained, and the visualization and controllability of the preparation process of the nanocarriers is realized, which facilitates the rapid optimization of the preparation parameters and provides objective, reliable and effective data at one time. In addition, the online monitoring technology can guarantee the uniformity of mass between batches in the production process of nanocarriers.

(3) Realizing environmentally friendly sample preparation: The system developed by the invention has an organic solvent and an inert gas recovery device, can effectively recover various organic solvents of different boiling points, and avoids organic solvent gas. The body is discharged into the air; in addition, the specially designed high-efficiency electrostatic collection device can achieve more than 90% effective collection of nanoparticles below 10 microns, avoiding the high bioactive powder particles floating in the air, giving the operator and surrounding The environment brings potential damage.

DRAWINGS

The advantages and features of the present invention will become more apparent from the detailed description of the invention read in the <

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic illustration of a high frequency ultrasonic nano-atomized particle preparation system in accordance with the present invention.

2 is a schematic view of a high frequency ultrasonic nano atomizing device in the high frequency ultrasonic nano atomized particle preparation system of the present invention.

3 is a schematic view showing the atomization shape of the ultrasonic atomizing nozzle in the high frequency ultrasonic nano atomized particle preparation system of the present invention.

4 is a schematic structural view of an efficient laminar flow electrostatic collecting device in a high frequency ultrasonic nano atomized particle preparation system according to the present invention.

FIG. 5 is a schematic diagram of an organic solvent and an inert gas recovery device in the high frequency ultrasonic nano atomized particle preparation system according to the present invention.

6 is a schematic diagram showing the principle of particle size analysis and dynamic image analysis in the multi-point dynamic nanoparticle real-time particle size and shape monitoring device according to the present invention.

7 is a schematic diagram of the principle of the automatic control and analysis prediction software according to the present invention.

Figure 8 is a schematic diagram of the connection between the automation control and the data integration process.

Reference numeral

1 Ultrasonic vibration nozzle 2 Control unit

4 flow rate regulator

5 syringe pump 6 liquid line

7 heater 8 cavity

9 porous metal foam board 10 drying chamber

12 electrode pads (-)

13 stainless steel collection tube 14 insulation

15 base 16 high piezoelectric generator

17 wires (+) 18 wires (-)

19

poles

20, 21 gas passage

22 first filter 23 heat exchanger

24 condenser 25 reservoir collection bottle

26 Safety relief valve 27 Oxygen content sensor

28 second filter 29 fan

30

flow meter

31, 32 gas

33 transducer 34 active electrode

35 Grounding electrode 36 Retainer

37 atomizing surface 38 nozzle

39 metal tube 41 heater controller

42 solid particles 43 refrigeration compressor

45 second path 46 third path

47 Fourth Path 48 Fifth Path

49 Nanoparticle real-time particle size monitoring device 50 Nanoparticle real-time shape monitoring device

51 software automation control and data integration processing device

detailed description

As shown in FIG. 1 , the high frequency ultrasonic nano atomized particle preparation system of the present application comprises: a high frequency ultrasonic nano atomizing device; a multi-point dynamic nano particle real-time particle size and shape monitoring device; an efficient laminar static electricity collecting device; a gas circulation and organic solvent recovery device; and an automated control and data integration processing device in which a liquid (solution, suspension or colloidal solution) can be atomized into a nano-sized droplet by a high-frequency ultrasonic nano-atomizing device; in the drying chamber 10 The inner layer is blown by the laminar drying gas, dried to be solid particles 42, and the solid particles 42 are collected in the static collector by the corona effect principle; the gas can be removed from the organic solvent recovery system to remove the organic solvent, thereby recycling the inert gas. The multi-point dynamic nanoparticle real-time particle size and shape monitoring device (49, 50) collects and calculates relevant parameters of the dried solid particles 42 and sends the obtained data and parameters to the automation control and data integration. a processing device (51) for establishing a solid particle by the automatic control and data integration processing device through multiple input of data and parameters Relational database parameters, and ultimately control the neural network model.

The high frequency ultrasonic nano atomizing device (Fig. 2), the high frequency ultrasonic nano atomizing device comprises a high precision positive displacement syringe pump 5, a flow rate regulator 4, an ultrasonic vibration nozzle 1 and a control unit 2; a control unit Electrically connected to the ultrasonic vibration nozzle 1 to provide an electrical signal, the syringe pump 5 through the pipeline and ultrasound The vibrating nozzle 1 is connected to supply a liquid, and the flow rate regulator 4 is connected to the syringe pump 5. 2, the ultrasonic vibration nozzle 1 includes a housing, a transducer 33, a metal tube 39, a nozzle 38, a holder 36 (for assembling a piezoelectric ceramic), an active electrode 34, and a ground electrode 35. One end of the metal tube 39 is The syringe pump 5 is connected by a liquid line 6, and the other end of the metal tube 39 forms a tapered nozzle 38. The transducer 33, the active electrode 34 and the ground electrode 35 are disposed on the metal tube 39 and fixed by the holder 36, and the control unit 2 is electrically connected to the transducer 33. Specifically, by using a control unit 2 that can change the frequency of 60 to 180 kHz and the control frequency is changed, the selected frequency is applied to the transducer 33 of the ultrasonic vibration nozzle 1 to vibrate, and the vibration is transmitted to be closely mounted thereto. On the metal tube 39 of the ultrasonic vibration nozzle 1 together, the metal tube 39 vibrates together at the frequency of the transducer 33 and amplifies the vibration frequency. The liquid (solution, suspension or colloidal solution) - is a conical mist that is delivered to the spout 38 of the ultrasonic vibration nozzle 1 by a high-precision positive displacement syringe pump 5 (see Fig. 1) to which the flow rate regulator 4 is connected. On the surface 37, the vibration frequency overcomes the surface tension of the liquid to form minute droplets, and the liquid sample is nano-atomized, and the solvent in the droplet is heated in the cavity 8 by the heater 7 to a certain temperature. The gas 31, 32 (the gas is selected from the group consisting of nitrogen, helium, carbon dioxide, and mixtures thereof) is instantaneously evaporated to form dry solid particles 42 (Fig. 4). This design can meet the needs of stable preparation of particles of different sizes. At the same time, since the frequency of the high-frequency ultrasonic nano atomizing device can be changed, it can be adapted to the atomization of different viscous samples.

The transducer 33 (Fig. 2) can be selected from any type of piezoelectric crystal. Under the action of the voltage applied by the active electrode 34 and the ground electrode 35, the piezoelectric ceramic wafer in the transducer 33 can be polarized and deformed to generate resonance. High frequency ultrasound. The liquid is supplied to the ultrasonic vibration nozzle 1 through a stable high-precision positive displacement syringe pump 5 (Fig. 1), and the liquid is subjected to high-frequency vibration on the surface of the atomizing surface 37 of the metal tube 39 of the ultrasonic vibration nozzle 1 to form minute droplets. The material is fully atomized. This can meet the needs of different viscosity samples and nanoparticle size. Preferably, the atomizing surface 37 of the ultrasonic vibration nozzle 1 of the high-frequency ultrasonic nano atomizing device (FIG. 2) can be designed as a surface of different shapes, and the shapes of different shapes of the surface after ultrasonic atomization are different, in order to The atomized droplets are brought into full contact with the

hot gases

31, 32, the solvent is rapidly evaporated, and sufficiently dried, and the atomizing surface 37 of the ultrasonic vibration nozzle 1 is selected as a conical surface (see Fig. 3). In addition, the high-precision syringe pump 5 used for the delivery of liquid can adjust the flow rate to adjust the uniformity of the atomized droplets.

An efficient laminar flow electrostatic collection system according to the present invention includes a cavity 8, a drying chamber 10, a laminar flow generating component, and an electrostatic collector. Wherein, the laminar flow generating member is composed of a porous metal foam plate 9 (Fig. 1, Fig. 4) disposed between the cavity 8 and the drying chamber 10 for partitioning the cavity 8 and the drying chamber 10; The electrostatic collector collects suspended powder particles in the gas by a corona effect, which is connected to the bottom of the drying chamber 10 and includes a stainless steel collecting cylinder 13, an electrode sheet 12 disposed in the stainless steel collecting cylinder 13, and a sleeve disposed on the stainless steel. The insulating layer 14 outside the cylinder 13, the stainless steel collecting cylinder 13 is a collecting electrode, and the electrode sheet 12 is a high-voltage discharge electrode (in which the electrode sheet 12 is disposed in the stainless steel collecting cylinder 13 through the strut 19); the ultrasonic vibrating nozzle 1 passes through the cavity 8 And the laminar flow generating member projects into the drying chamber 10. The nano-droplets are carried by a drying gas (selected from nitrogen, helium, carbon dioxide, and mixtures thereof) through the drying chamber 10 and into the electrostatic collection system. The laminar gas of this system is produced by a porous metal foam board 9. The porous metal foam plate 9 is composed of a metal skeleton and pores. Since a large amount of pores are present inside, when a high velocity gas (cycle gas in the drawing) 31, 32 hits the porous metal foam plate 9, the gas enters the porous metal foam plate 9. The pore channels, thereby reducing the gas flow rate, eventually form a laminar flow rather than a turbulent gas flow (Fig. 4) to prevent the dry particles from adhering to the inner wall of the drying chamber 10. The electrostatic collecting member of this system is disposed below the drying chamber 10 (Figs. 1 and 4), which is an electrostatic collector that collects powder particles suspended in the gas by a corona effect (wherein the electrostatic collector has a base 15), which There is a need for an adjustable voltage DC high voltage generator 16 connected by a wire (+) 17 and a wire (-) 18; an electric field that separates an electric field that charges the particles in the gas from the charged powder particles; It is through two electrodes having positive and negative, one is a discharge electrode (electrode sheet 12 as a discharge electrode), one is a collection electrode, and the collection electrode is a cylindrical tube type (a stainless steel collection tube 13 of an electrostatic collector is used as a collection electrode), Corona discharge is generated between the positive and negative electrodes. Under the action of the electric field, when the gas carrying the solid particles 42 passes through the electrostatic collector, a negative charge is obtained, which is deposited on the stainless steel collecting cylinder 13 of the electrostatic collector of the anode. The electrostatic collector uses a star electrode to enhance the discharge.

According to the inert gas circulation and organic solvent recovery system (Fig. 5) of the present invention, the inert gas circulation and organic solvent recovery system includes a first filter 22 (for removing large particles in the gas), a heat exchanger 23, a condenser 24, a liquid storage collection bottle 25, an oxygen content sensor 27, and a second filter 28 (containing activated carbon for adsorbing an organic solvent in the gas), and the lower end of the heat exchanger 23 passes through the first passage 44 and the high efficiency layer The flow static electricity collection system is connected, the first filter 22 is arranged in series on the first passage (the first passage is the gas passages 20, 21); the lower end of the transducer 33 is connected to the second filter 28 through the second passage 45; The upper end of the heat exchanger 23 is connected to the lower end of the condenser 24 through the third passage 46; the upper end of the heat exchanger 23 is connected to the upper end of the condenser 24 through the fourth passage 47, and the liquid storage collection bottle 25 is connected to the condenser 24. An oxygen content sensor 27 is disposed on the second passage 45; the second filter 28 is connected to the cavity 8 through the fifth passage 48, and the fifth passage 48 is sequentially provided with the blower 29 from the one end connected to the second filter 28 a heater 7, which is provided with a heater 7 for controlling the heater 7 temperature Degree of heater controller 41. A flow meter 30 is disposed on the fifth passage 48 between the blower 29 and the heater 7. A condenser compressor 43 is disposed on the condenser 24, and a safety relief valve 26 is further disposed on the condenser 24. In a preferred embodiment, when a gas containing a gaseous organic solvent (for example, ethanol, dichloromethane, chloroform) is passed through the condenser 24, it is cooled to a temperature below the boiling point of the organic solvent with chilled water, and the organic solvent is condensed into a liquid. After passing through the condenser 24, the organic solvent is separated and introduced into the liquid storage collection bottle 25. Then, the separated gas is purified by a second filter (activated carbon filter) 28, and returned to the high-frequency ultrasonic nano atomizing device. At the same time, the closed loop of the inert gas circulation and organic solvent recovery system operates in an inert gas atmosphere to prevent the production of any explosive mixture. The system is equipped with an oxygen content sensor to monitor the oxygen concentration at all times to ensure that the spray drying system can be low. Operate in an oxygen environment.

The multi-point dynamic nanoparticle real-time particle size and shape monitoring device (see FIG. 6) of the present invention combines dynamic image analysis technology by monitoring the size and distribution of particles by using light diffraction or scattering techniques (such as laser diffraction). The morphology of the particles is monitored. By comprehensively analyzing the particle size and roundness data of the dried particles 42 obtained by the in-line monitoring device, an indication of adjusting the sample delivery parameters, the ultrasonic vibration nozzle 1 parameters, or the dry gas parameters is obtained. Further, combined with the automatic control device (51), the association database of granularity, granular shape and control parameters is established through multiple data and parameter input, and finally the neural network control model is established, and the rapid feedback of analyzing product quality information and adjusting specific control parameters is realized.

Software automation control and data integration processing device (see FIG. 7) according to the present invention, parameters such as ultrasonic atomization power and frequency, injection pump flow rate, heating temperature control, inert gas circulation flow rate and pressure, and electrostatic generator voltage Control, through data analog control, serial communication and TCP/IP communication mode, achieve precise control according to the control model; realize high-speed data transmission and storage through the combination of optical communication and internal high-speed bus; through the theory of processing related data And algorithm analysis, design and implementation of related algorithms; design and implement dynamic image processing algorithms according to the standards of dynamic image analysis; integrated analysis of dry nanoparticle size and morphology data; finally, the effect of various parameters on the quality of nanoparticles , to form statistical results and trend predictions, giving an intuitive image/chart display. Software functions include control functions, device management functions, data transmission and storage functions, data processing functions, statistical analysis functions and other modules, running in the PC environment, support WINDOWS 7, Windows XP and other operating systems; support mobile terminal test results push function.

Claims

A high frequency ultrasonic nano atomized particle preparation system with dynamic monitoring function, characterized in that the system comprises:

a high-frequency ultrasonic nano atomizing device, wherein the liquid is atomized into nanometer-sized droplets by the high-frequency ultrasonic nano atomizing device;

a laminar electrostatic collection system for drying the nano-sized droplets into solid particles by blowing a laminar drying gas, and collecting the solid particles in an electrostatic collector;

An inert gas circulation and an organic solvent recovery system, the drying gas is removed from the system by the inert gas circulation and the organic solvent recovery system to realize the recycling of the inert gas;

A multi-point dynamic nanoparticle real-time particle size and shape monitoring device, which collects and calculates relevant parameters of dried solid particles and sends the obtained data and parameters to an automatic control and data integration processing device;

The automated control and data integration processing apparatus establishes an associated database of solid particle parameters by the plurality of inputs of the data and parameters, and establishes a neural network control model.
The high frequency ultrasonic nano atomized particle preparation system with dynamic monitoring function according to claim 1, wherein the high frequency ultrasonic nano atomizing device comprises a high precision positive displacement syringe pump, a flow rate adjuster, and an ultrasonic vibration nozzle And a control unit; the control unit is electrically connected to the ultrasonic vibration nozzle to provide an electrical signal thereto, the syringe pump is connected to the ultrasonic vibration nozzle through a pipeline to provide liquid thereto, and the injection pump is connected to the Flow rate regulator.
The high-frequency ultrasonic nano-atomized particle preparation system with dynamic monitoring function according to claim 1, wherein the multi-point dynamic nanoparticle real-time particle size and shape monitoring device uses a light diffraction or scattering technique to measure particle size and The distribution is monitored while the dynamic image analysis is combined to monitor the morphology of the particles for the collection of the relevant parameters.
The high frequency ultrasonic nano atomized particle preparation system with dynamic monitoring function according to claim 1, wherein the high efficiency laminar flow electrostatic collection system comprises a cavity, a drying cavity, a laminar flow generating component and an electrostatic collector; The laminar flow generating member is composed of a porous metal foam plate that collects powder particles suspended in a gas by a corona effect, the laminar flow generating member being disposed between the cavity and the drying chamber for separating the a cavity and a drying chamber; the electrostatic collector is coupled to a bottom of the drying chamber; the ultrasonic vibration nozzle extends through the cavity and the laminar flow generating component into the drying chamber.
The high-frequency ultrasonic nano-atomized particle preparation system according to claim 4, wherein the electrostatic collector comprises a stainless steel collecting cylinder, an electrode sheet disposed in the stainless steel collecting cylinder, and a sleeve The stainless steel collection tube is an insulating layer outside the cylinder, the stainless steel collecting cylinder is a collecting electrode, and the electrode sheet is a high voltage discharge electrode.
The high frequency ultrasonic nano atomized particle preparation system according to claim 4, wherein the inert gas circulation and organic solvent recovery system comprises a first filter, a heat exchanger, a condenser, a liquid collection bottle, and an oxygen content sensor. And a second filter, the lower end of the heat exchanger being connected to the high-efficiency laminar flow electrostatic collection system through a first passage, the first filter being serially disposed on the first passage; the heat exchanger a lower end is connected to the second filter through a second passage; an upper end of the heat exchanger is connected to a lower end of the condenser through a third passage; an upper end of the heat exchanger passes through a fourth passage and the condenser An upper end connection, the liquid collection bottle is connected to the condenser, the second passage is provided with the oxygen content sensor; and the second filter is connected to the cavity through a fifth passage The fifth passage is provided with a fan and a heater in series from one end connected to the second filter.
The high frequency ultrasonic nano atomized particle preparation system according to claim 2, wherein the ultrasonic vibration nozzle comprises a casing, a transducer, a metal pipe, a spout, a holder, an active electrode, and a ground electrode, the metal pipe One end is connected to the syringe pump through a liquid line, and the other end of the metal tube forms a tapered nozzle, and the transducer, the active electrode and the ground electrode are disposed on the metal tube and pass the fixing The device is fixed, and the control unit is electrically connected to the transducer.
The high frequency ultrasonic nano-atomized particle preparation system according to claim 6, wherein the condenser is a low temperature coil condenser, a plate heat exchanger or a tube plate heat exchanger.
The high-frequency ultrasonic nano-atomized particle preparation system according to claim 6, wherein the second filter uses a porous solid adsorbent for adsorption-desorption to separate the inert gas.