Current Status and Prospects of Fluidized Bed Technology in Pharmaceutical Industry

Fluidized bed is also called fluidized bed. The application of fluidized bed technology in China's pharmaceutical industry should be traced back to the 1980s, from the original fluidized bed drying to fluidized bed mixing, fluidized bed coating, fluidized bed system. The application of granules (pellets) and fluidized bed pulverization has progressed from the original solid preparation to other preparations in formulation application, and has made outstanding contributions especially in granulation drying. It can be said that the fluidized bed technology is of great significance for the development of China's pharmaceutical industry. The fluidization performance of the fluidized bed to the material will extend more applications, and now it is necessary to carry forward this classic technology. This paper starts with the basic concept of fluidized bed, analyzes and compares the current situation of fluidized bed application in the pharmaceutical industry, and also expounds the characteristics of several fluidized bed equipment, and at the same time smashes the development and application prospect of fluidized bed technology.

1 basic concept of fluidized bed
1.1 The concept of fluidization phenomenon In a device, the granular material is stacked on the distribution plate. When the gas is introduced into the bed from the lower part of the device, the gas velocity is increased to a certain extent, and the solid particles are boiled on the bed. This state is called fluidization, and this bed is also called a fluidized bed. The use of such a method in addition to other techniques can complete the functions of drying, granulating, mixing, coating and pulverizing the materials.
Due to the different characteristics of the solid particulate material, as well as the bed and gas flow rate and other factors, the bed can exist in three forms as shown in Figure 1.
V< Vmf V≥Vmf Vmf< V < Vt V≥Vt
Dead bed fluidized bed fluidized bed (1)* stage (fixed bed), when the fluid velocity is low, the solid particles in the bed are in contact with the fluid, but the corresponding positions of the solid particles do not change. The state of the particles is a fixed bed;
(2) In the second stage (fluidized bed), when the fluid flow rate in the fixed bed stage is gradually increased to a certain point, the solid particles will move to each other. If the fluid velocity is increased, the pressure loss of the bed is maintained. Unchanged, the solid particles will produce irregular movement in the bed, and the bed will be fluidized at this time;
(3) The third stage (air flow transport), when the fluid flow rate is greater than the settling speed of the solid particles, then the solid particles cannot continue to stay in the container and are carried out of the container by the gas stream.
For pharmaceutical industry applications, drying, granulation, mixing, coating, etc. are operated in the second stage, and the second stage and the third stage are used for the pulverization.
1.2 The concept of fluidized fluidization is divided into scattered and polytypes, and most of the fluidized beds encountered in the fluidized bed are polyfluidized. In the fluidized state of the polymer, the solid particles do not appear in a single form but in the form of a particle group. When the fluidization technology is used in the pharmaceutical industry, the density of solid particles and fluids generally differs greatly (such as the density of hot air and inert gases). In actual application, the process parameters and equipment design are not easy to cause "channeling" and "surge" phenomenon as shown in Figure 2.

Ditch flow (1) "channel flow", when the fluid flows into the fixed bed, the fluid is unevenly distributed in the bed due to various reasons, causing a short circuit in a local part of the bed, allowing a considerable amount of fluid to pass. A short circuit flows through the bed. If a "channel flow" is generated, the fluidized bed drying equipment will cause poor contact between the drying medium and the material to be dried, and the drying effect is lowered.
(2) “Tengyong”, when the particle size distribution in the fluidized bed is uneven, the gas distribution is extremely uneven, and the height and diameter of the fluidized bed are relatively large, the bubbles inside the bed will merge and grow until the bubbles When the diameter is large enough to be close to the inner diameter of the bed, the solid particles form a piston moving upward in the bed, the particles will be thrown up very high, the small particles are entrained by the air flow, and the large particles then fall. Such a cycle also causes poor contact between the solid particles and the drying medium fluid, and the drying effect is lowered.
2 Fluidized bed technology and equipment in the pharmaceutical industry, the current situation of fluidized bed technology Zui used in the drying industry was established in 1948 in the United States Dole-Oleph solid fluidization device, and China began to apply after 1958 Fluidized bed technology, first applied in the salt industry, has been widely used in fertilizers, pigments, plastics, pharmaceuticals, etc., where its true application in the pharmaceutical industry was after 1980, when it was only used in solid preparations. Dry. Nowadays, fluidized bed technology has developed from simple fluidized bed drying to fluidized bed coating, fluidized bed pelleting, fluidized bed mixing and fluidized bed pulverization in the pharmaceutical industry, especially in recent years, it has been extended to coating and manufacturing. Granule (pill) function, the new function shows more advantages than the original traditional preparation process.
2.1 Analysis of current status of fluidized bed drying technology and equipment
2.1.1 Analysis of fluidized bed drying characteristics Fluidized bed drying uses hot air flow to suspend wet particles. Fluidized boiling causes heat exchange of materials, taking moisture away to dry, and using hot air flow to gas-solidize materials. The mass transfer of the two-phase suspension contact reaches the wet particle drying.
2.1.1.1 Advantages of fluidized bed drying (1) Due to the large contact area between the material and the drying medium, and the material is continuously stirred vigorously in the bed, the heat transfer effect is good and the temperature inside the bed is relatively uniform and high. The heat capacity coefficient (or volumetric heat transfer coefficient) can generally reach 8000~25000kJ/(m3·h·°C), and has the characteristics of large production capacity;
(2) It is especially suitable for drying certain heat sensitive materials due to uniform temperature distribution in the fluidized bed, thereby avoiding any local overheating of the product;
(3) Continuous operation can be performed in the same equipment, and intermittent operation can also be performed;
(4) The residence time of the material in the dryer can be adjusted as needed, so the moisture content of the product is stable;
(5) The drying device has fewer moving parts, so the investment cost of the equipment is low, and the maintenance workload is small.
2.1.1.2 Disadvantages of fluidized bed drying (1) The granularity of the material to be dried has a certain degree. Generally, it is not less than 30 micrometers, and not more than 4 millimeters is suitable. The particle size is too small to be entrained by the airflow, and the particle size is too large to be fluidized;
(2) When several materials are mixed and dried, the relative density of several materials is required to be close;
(3) Materials with too high water content and easy to bond into a group are generally not applicable, and at the same time, materials that are easy to form walls and easy to bond groups will cause walling and plugging in the fluidization process;
(4) Due to the intense backmixing of the fluidized dryer, in the single-stage continuous fluidized drying device, the material residence time is not uniform, and it is possible that the un-dried material is discharged out of the bed along with the product.
2.1.2 Analysis of the current status of fluidized bed drying equipment Fluidized bed drying, also known as boiling drying, uses hot air flow to suspend wet particles, fluidized boiling to heat the materials, and take the moisture away to dry. The utility model adopts a convection drying method, and the gas-solid two-phase large-area contact shows the characteristics of boiling temperature difference such as small temperature difference of the material bed, fast drying speed and uniform water content of the finished product, and is widely applicable to varieties with large yield. Fluidized Bed Drying Equipment Applications In the pharmaceutical industry, there are often horizontal fluidized bed dryers, high efficiency boiling dryers, and the like.
2.1.2.1 Fluidized Bed Dryer The fluidized bed dryer consists of an air filter, a heater, a fluidized bed main engine, a cyclone separator, a bag filter, a high-pressure centrifugal fan, and a console as shown in FIG. When the granular solid material is added to the fluidized bed dryer by the feeder, the filtered clean air is heated and sent to the bottom of the fluidized bed by the blower to contact the solid material through the porous distribution plate to form a gas-solid heat exchange. After the material is dried, it is discharged from the discharge port, and the exhaust gas is discharged from the top of the boiling bed through the cyclone dust collector group and the bag filter to recover the solid powder and then emptied.
The bubbling bed dryer is capable of continuous feeding and discharging, and has the characteristics of large output. It is mainly used in the production of traditional Chinese medicine granules. However, its production effect is not satisfactory, the main reasons are: (1) the original structural design is flawed, the structure is not effective to avoid cleaning dead corners and blind spots; (2) in the true sense of the continuous feed and discharge requirements.
There are many imitations in this type of machine, but they are inseparable from the two foreign representative models. One type of representative is the United States Ventilex, which has achieved a single machine evaporation of 5000kgH2O/h; the other is the German Glatt GF. The series products have reached a single machine evaporation capacity of 1600 kgH2O/h. The main differences between domestically produced models and these two types of equipment are: (1) zero-pressure design and control of the bed; (2) dust recovery device and series design; (3) quick disassembly structure designed for cleaning SOP; 4) An effective recovery device for organic dissolved coal.
2.1.2.2 High-efficiency boiling dryer As shown in Fig. 2, after the air is purified by heating, it is introduced from the lower part by the induced draft fan and passes through the porous stencil of the hopper. In the working chamber, fluidization is formed by stirring and negative pressure, and the moisture is quickly evaporated and then taken away with the exhaust gas, and the material is quickly dried. The high efficiency boiling dryer features:
(1) The fluidized bed has a circular structure to avoid dead ends;
(2) Stirring is set in the bed to avoid the agglomeration of the wet materials and the formation of channel flow in the drying process;
(3) It is convenient, quick and thorough, easy to operate and easy to clean.
(4) Sealed negative pressure operation, no dust leakage;
(5) The drying speed is fast and the temperature is symmetrical. The drying time of each batch is generally 20-30 minutes.
This model is designed for wet granule drying. Due to its simple structure and low price, it is widely used in Chinese pharmaceutical factories, and the proportion of foreign countries is very small. The problem to be solved by the machine is that due to the built-in stirring structure, the sealing and quick-discharging cleaning should be overcome.
2.2 Analysis of current status of fluidized bed granulation (pill) technology and equipment
2.2.1 Analysis of fluidized bed granulation (pill) characteristics Fluidized bed granulation is formed by auxiliary binder spraying process in fluidized bed drying process. Fluidized bed granulation is also called one-step granulation. , granulation, drying in one. The principle is that the particles are fluidized and mixed by the action of the gas stream. The adhesive is sprayed on the powder by airflow spray to agglomerate, and the hot air flow is used to carry out the heat transfer of the material by gas-solid two-phase suspension contact to achieve particle drying.
2.2.1.1 Advantages of fluidized bed granulation (1) Integrating mixing-granulation-drying, the mixing time, product moisture content, granulation quality and uniformity after drying meet the corresponding requirements;
(2) The granulated finished granules are relatively loose, with a particle size of about 20 to 80 mesh, and the appearance of the finished product is approximately spherical, and the fluidity is good;
(3) High production efficiency and low labor intensity;
(4) The mixing, granulating and drying processes should be under the condition of fully enclosed negative pressure to prevent dust pollution and flying, and the external pollution is low.
2.2.1.2 Disadvantages of fluidized bed granulation (1) High power consumption;
(2) It is relatively difficult to clean up;
(3) Improper control is likely to cause pollution.
The pneumatic swirling fluidized bed developed in recent years can be both granulated and coated. At the same time, centrifugal fluidized bed pellets can produce porous spherical particles or pellets, which are suitable for mass production of high density small diameter pellets. Since these techniques can complete the coating while fluidizing granulation or pelletizing, this point is included in the 2.3 fluidized bed coating section.
2.2.2 Analysis of current status of fluidized bed granulation (pill) equipment
2.2.2.1 Boiling Granulator The boiling granulator (also known as the one-step granulator) is a device that integrates mixing-granulation-drying as shown in Fig. 5. The boiling granulator is a granulating equipment widely used by pharmaceutical companies at present, and its process is becoming more and more mature. At present, more than 70 units in China have produced such equipment. Boiling granulator features:
(1) The inlet air adopts 2~3 grade filtration, and the induced draft fan is equipped with silencer. The whole mixing, granulating and drying process is completely closed from the inlet, atomization and exhaust.
(2) The spray pressure and particle size of the machine, the temperature of the inlet and exhaust air and the air volume, the negative pressure, the amount of binder and the concentration should meet the actual process requirements, and the granulation can be quickly dried and uniform;
(3) using a multi-fluid atomizer, and the entire adhesive spray has program control;
(4) The pressure difference between the two ends of the filter bag of the dust collection bag can be automatically detected and controlled, so that the bed is kept in a fluidized state;
(5) Double-collection filter bag system, complete cleaning.
Internationally, such equipment is represented by GLATT and Aeromatic's corresponding products. Compared with the international advanced technology, the domestic boiling granulator has a big gap, mainly in the following aspects:
(1) The design of the medium pretreatment device has been included in the one-step granulation process recommended by GLATT and Aeromatic, and has not been designed in China at present;
(2) In terms of accessory selection, foreign equipment adopts a high-strength anti-static cloth filter bag with high strength, low dust removal effect, long wind resistance and durability, but there is no such product in China at present;
(3) In terms of control, foreign equipment can achieve process repeatability, control chain error with feedback of various relevant process parameters, and variable error design matching process requirements. The process repeatability is extremely strong, and the domestic demand is not met. ;
(4) In terms of structure, the design and production process of foreign equipment strictly abides by GMP regulations, such as the discharge of cleaning fluid, the sealing of moving (static) parts, and the fluidized dead angle of the flange are reasonable and effective, while most of the domestic In terms of product design and design, strictly speaking, there is still a distance from the GMP standard.
However, internationally represented by GLATT and Aeromatic's corresponding products, its products occupy an absolute share in the world. Although the products are advanced, there are still some imperfections. For example, the application range of foreign products is narrow, and the models are biased to single varieties. However, there are many varieties in China's pharmaceutical factories, so technical design should be considered for more versatility. In addition, the standard type of the original imported model mapping is poorly versatile.
2.2.2.2 Continuous fluidized bed granulator Continuous fluidized bed granulator As shown in Figure 6, the technique of dissolving spray and gas stream classification in the traditional boiling dry flow technology is a derivative of fluidized bed equipment. Its characteristics:
(1) Using fluidized cooling (drying), the mass heat transfer is fast;
(2) Spraying granulation, the product strength can be controlled;
(3) Classification of the gas source system, the particle size range of the finished product is extremely small;
(4) Continuous granulation operation with high production efficiency.
It is mainly used for powder material mixing, drying, granulation, granule "spraying", enlargement, melt cooling granulation and other operations in the pharmaceutical, food, chemical and other industries.
2.3 Analysis of current status of fluidized bed coating technology and equipment
2.3.1 Analysis of technical characteristics of fluidized bed coating Fluidized bed coating is in the process of fluidization, all particles are suspended in the fluidized gas stream, the surface is completely exposed, various coating liquids can be sprayed, and damp heat is applied. exchange. Among them, the fluidization state is determined by the characteristics of the fluidized material and the structure of the equipment, and the fluidization state is different for each technology. There are three types of spray technology for coating, namely top spray (standard bed), bottom spray (Wurster) and side spray (rotor). In order to make the film uniform and continuous, try to reduce the droplet travel (ie liquid The distance from the outlet of the nozzle to the surface of the particle) to reduce the spray drying effect of the hot air on the droplet, so that when the droplet reaches the surface of the coated particle, it can basically maintain its original characteristics to achieve uniformity and ideal spreading. Uniform continuity of sex and film.
2.3.1.1 Characteristics of top-spray fluidized bed coating The top-flow fluidized bed usually has a conical shape, the spray gun has a low position at the fluidization interface, and the fluidized gas flows through the bottom screen into the trough. Increased, the original stationary material is fluidized by the airflow. Wherein, the particles are accelerated by the airflow to accelerate from the trough through the nozzle, and the nozzle sprays the coating liquid onto the surface of the irregular moving material in a direction opposite to the moving direction of the particles. Top-jet fluidized bed is prone to two major problems:
(1) Reverse spray will increase the distance from the nozzle to the particle surface, and the hot air will also increase the volatilization of the droplet, thus affecting the viscosity, spreadability and film formation of the droplet;
(2) The irregular fluidization state cannot effectively control the uniformity of the movement of the droplets to the encapsulated particles.
The advantages of the top-spray fluidized bed technology are: large batch size, easy installation and convenient batch change cleaning. The disadvantages are: narrow application range, easy adhesion of particles and unsuitable coating of particles.
2.3.1.2 Characteristics of the bottom-spray fluidized bed coating The bottom-spray fluidized bed coating was founded in 1959 by Dr. Dale Wurster of the University of Wisconsin. The basic principle is: spray fluidization combined with spray to form a fountain The state makes the industrial coating become a reality, and the extensive use of its technology has not been compared to other forms. An atomizer is arranged in the center of the distribution plate of the fluidized bed coating device, that is, a bottom fluidized bed (also called a Wurster system), wherein a center of the material bed with the expansion chamber is provided with a circular guiding cylinder, and the distribution plate is in the guiding cylinder region. It has a large opening ratio to meet most of the air volume, forming a fountain-like fluidization. The powder particles are accelerated from the guiding cylinder by the airflow, and then leave the guiding cylinder to enter the expansion chamber, and then the wind speed drops sharply. The material falls into the annulus region between the bed and the guide cylinder, such a cycle. The material is highly dispersible, and the bottom spray coating process has the desired process repeatability. The two process characteristics of the bottom spray fluidized bed coating are:
(1) The same direction spray will make the direction of the spray consistent with the direction of particle movement, and this movement is fast, continuous and uniform;
(2) The coating liquid is sprayed on the surface of the moving particles near the nozzle, so the distance from the droplet to the surface of the coated particles is very short, and it is easy to form a continuous and tight film.
Advantages of bottom-spray fluidized bed coating: good film quality, wide application range and medium-volume production. A disadvantage of the bottom spray fluidized bed coating is that the porous plate in the machine needs to be replaced when the process changes.
With the rise of new pharmaceutical processes such as pellet preparation and controlled release coating, the pellet preparation and the controlled release coating are used to mask taste, color, moisture, oxidation, shading, stomach dissolution, heat insulation, enteric dissolution, The characteristics of sustained release and controlled release determine the market for the corresponding equipment. In China, the bottom spray Wurster system is a widely used device for the preparation of pellets and controlled release coatings. Often, such equipment is a combination of pellets and coatings. In China, I am the first to apply for a patent. At present, the output of our company's products ranges from 150g/batch to 200kg/batch. Users use up to 65 homes for slow release products from powder coating to pellets.
2.3.1.3 Characteristics of side-spray fluidized bed coating The side-spray fluidized bed coating is a relatively new technology. The principle of side-jet fluidized bed coating is: the material tank is cylindrical and the bottom has a variable speed. The turntable and the turntable can be moved up and down to adjust the intake air amount, and the coating liquid is fed into the trough through the atomizing nozzle on the wall of the trough. The spray direction of the nozzle is consistent with the direction of fluidization of the particles, and the coating liquid is tangentially injected. Inside the trough. The movement of the particles in the trough is spin-like, uniform and orderly, due to the three forces of synthesis, namely the gravity of the particles themselves (the downward movement of the guiding particles), the upward airflow through the gap (making the particles upward Movement) and the centrifugal force generated by the rotation of the turntable (moving the particles around the turntable), these three forces are combined to cause the particles to move in a spiral shape. The three process characteristics of the side-spray fluidized bed coating are:
(1) in the same direction, the nozzle is buried in the material, so that the droplet stroke is short;
(2) The probability of mixing of particles and spray atomization is equal;
(3) The particles are highly concentrated in the spray area.
The side-spray fluidized bed coating is comparable to the bottom-spray fluidized bed coating. The disadvantage is that it produces large mechanical friction and is not suitable for brittle materials. Side-spray fluidized bed coatings are commonly used to produce large quantities of pills, as well as for slow, controlled release coatings.
2.3.1.4 Comparison of top spray, bottom spray and side spray forms For the three spray methods of top spray, bottom spray and side spray, each has its own characteristics in fluidized bed coating. As shown in Table 1, it can be seen that with the development of modern formulation processes, a single bed type cannot meet the requirements.

Table 1 machine spray bottom spray side spray 3 ways to compare bed type air volume material dispersive fluidized material friability degree dry rate granulation porosity use top spray large medium random high fast large granule bottom spray high rule low medium and medium package Side spray small low regular low low low coating, granulation (pill)

2.3.1.5 Cyclone fluidized granulation coating Swirling fluidized granulation coating technology originated from Huttlin, Germany, the first Kugelcoater multi-functional granulation coating machine to use the "turbine drive chassis", three spray fluidized bed Organic combination is the great achievement of the new technology of fluidization. According to its principle and actual national conditions, Changzhou Jiafa Granulating Drying Equipment Factory developed the LBF swirl fluidized bed granulation coating machine in 2002. The powder or granules in the fluidized bed are subjected to the buoyant air buoyancy, the rotating centrifugal force and the self-gravity, and are in the form of a ring-shaped strand. The binder or coating liquid is sprayed into the layer to form a true sphericity and a high pellet. A continuous or uniform film of the film in which the rotor speed is continuously controllable. The pellets are in a panicle state in the bed, resulting in a dense surface, true sphericity and high.
(1) The swirling fluidization and top spray granulation comparison are shown in Table 2:

Table 2 Cyclone fluidization and top spray granulation control model boiling granulator spray drying granulator cyclone fluidized bed granulation coating machine Banlang extract: sugar powder 1:3 1:3 1:3
Initial feeding 96 120 120
Extract γ=1.2g/cm3 γ=1.2g/cm3 γ=1.2g/cm3
Granulation time 100min 75min 52min
Particle size 30-60 mesh
77% 30-60 mesh
82% 10-40 mesh
91%

(2) Compared with the wurster bottom spray coating, the swirling fluidized bed coating does not need to be limited in the spray range. The mist particles are expanded in the material layer, and multiple gun operations can be set. The swirling fluidized bed coating is related to the process parameters. as shown in Table 3:

Table 3 Swirling fluidized bed coating process parameters material cefotaxime hydrochloride itraconazole omeprazole phytase citrate acid diltiazem coating function to taste the stomach soluble sustained release to maintain active moisture control Weight gain 15% 64.2% 25% 8.5% 5% 25%
Membrane Eudragit
E100 Eudragit
E100 HPMCP HPMC HPMC Eudragit
RS100
Inlet air temperature (°C) 55 53 47 45 60 40
Finished product size (mesh) 40~80 20~25 20~30 14~40 10~30 18~24

2.3.2 Analysis of the current status of fluidized bed coating equipment (1) (bottom spray) fluidized bed coating machine fluidized bed granulation coating machine shown in Figure 7 is the use of bottom spray fluidization mechanism to control materials in The bed is opened in an orderly motion to achieve precise granulation and coating functions. It can be applied: powder coating of ≥μ50m, granules, pellets (≤6mm) taste masking, coloring, hot melt, moisture proof, antioxidant coating, pellet enteric coating, sustained release coating, controlled release coating, suspension Liquid, solution coating amplification, etc. Its characteristics:
(1) The material is highly dispersed, and the material is in the state of airflow transportation in the guiding cylinder, and the dispersibility is good, accompanied by the spraying of the coating film, so as not to cause adhesion;
(2) Bottom spray, the fog particles run in the same direction as the material, the distance to the material is very short, the moisture is not evaporated quickly, and the material is well adhered, and has a strong spreadability, so that the film is firm, continuous;
(3) The fluidization of the regular flow pattern, the fountain fluidization can make the materials in the equipment have a reproducible running track, which is indispensable for the strict coating operation, and the purpose is to make the material and the fog particles The exposure will be equal and the coating will be uniform. At the same time, the material itself forms a rotation, and the angle of contact with the fog particles at any angle on the surface is equal. Therefore, for sustained release and controlled release, the film formed by the bottom spray process is continuously uniform;
(4) Film properties, the regular flow of the fountain in the bottom jet fluidized bed makes the "complete" coating feasible, and has the characteristics of less consumption of clothing and uniform film;
(5) In terms of structure, first, the height of the guiding cylinder is adjustable. As the particle size of the material becomes larger, its height will change. Second, the fluidized distribution plate changes with the nature of the material, and its opening ratio and its distribution. The replacement method is adopted; the third is the proper design of the height of the guiding cylinder. According to the height of the “dead bed”, the design height is too high, the collision is intensified, and the “coating layer” will fall off. The height design is too low, which will affect the material flying from the fluidized area to the package. The clothing area migrates, causing uneven coating;
(6) Industrialization amplification, the bottom spray bed can complete the coating operation of 400g to 500kg. In the large production, the bed is set to 7 nozzles, and it can simultaneously require seven consistent fountain streams. Our company can already use LDP-120. The fluidized granulation coating machine type nozzles are installed up to five. In the chemical industry, Changzhou Jiafa has successfully produced several 1000kg/batch bottom spray coating fluidized bed equipment.
2.3.2.2 Multi-functional granulation coating machine Multi-functional granulation coating machine As shown in Fig. 8, it is a multi-functional device integrating spray drying granulation-centrifugal coating-fluid coating-drying. The machine is compatible with a variety of process operations, especially suitable for multi-variety, multi-dose granulation, pelleting and coating in the pharmaceutical, food, chemical and other industries. It can prepare granulation and coating of powder materials; prepare 50μm particles and package Preparation of porous instant-soluble granules, multi-layer sustained-release controlled release coating, spherical granulation and coating; granulation and coating of Chinese patent medicine flow extract; preparation of dense sphere (pill) shaped granules and coating; Granular, agglomerated materials are dry. Its characteristics:
(1) A multi-purpose machine is realized by interchanging a fluidized bed;
(2) completing granulation, pelleting, coating and drying operations on a machine;
(3) Serialization, there are many models of FLP1~FLP120;
(4) Ideal equipment for the development of new drugs.
2.3.2.3 Cyclone fluidized granulation coating machine Cyclone fluidized granulation coating machine is shown in Figure 9. The principle is as follows: after the air is purified, the heater is heated to the operating temperature, and the vortex-flowing blade is irradiated. The tangential entry into the fluidized bed drives the material in the bed to form a swirling flow. Due to the buoyancy of the airflow, the material is simultaneously tumbling. In this state, the material is in suspension and its surface area is completely exposed to the gas phase for rapid heat and mass transfer convection. Dry, water is discharged through the filter with the exhaust air, and the airflow atomizer ambushed on the drive plate sprays in the same direction along the airflow direction. The powder is wetted and aggregated, bridging or granulating in the powder (pill) The surface is coated, spread into a film, and the coating operation is completed. The cyclone fluidized granulation coating machine can be applied to powder particles, particle coating, pelleting, coating, etc., and is particularly suitable for making dense particles (increasing specific gravity), and also for producing large particles (8-20 mesh).
2.3.2.4 Characteristics of cyclone fluidized granulation coating machine (1) Characteristics of radiant air inlet drive disk, hot air enters tangentially with radiation, material moves in three dimensions, and it is faster to mix with top spray fluidized bed. Produce stratification. The material is rotated and tumbling in the bed, which is more regular than the top spray, thus facilitating uniform coating of powder, granules and pills. While the material is running in the bed, it produces self-rotation, and the surface film thickness is uniform, so it can be applied to the slow-release coating. At the same time, the rotating fluidized material is extruded between the materials, and the granulation density is high, which is particularly desirable for granulation requiring a large specific gravity for filling. In addition, the material swirling and self-rotating, the granulation degree is high, and the appropriate auxiliary material ratio can complete the pellet preparation operation.
(2) The characteristics of the atomizer are three-fluid atomizer, the inner layer gas is used for atomization, and the outer layer gas is used to isolate the atomization area from the material at the outlet to ensure no adhesion. The atomizer is buried in the material layer for the bottom spray operation, the distance from the mist particles to the surface of the material is extremely short, the binder can fully wet the material, and the granulation time is shortened. At the same time, the atomizer is buried in the bottom of the material layer. The distance between the fog particles and the surface of the material is extremely short. When coating, the fog particles will not form spray drying, ensuring complete utilization and low production cost. , production efficiency is improved.
(3) The characteristics of CIP cleaning in place, 360° rotating fast cleaning head can realize quick cleaning operation in the host. At the same time, the stainless steel sintered filter does not need to be disassembled for cleaning.
(4) The characteristics of the inlet and outlet, using the induced draft fan, the negative pressure airflow to feed the material to avoid dust flying. At the same time, the centrifugal state generated by the rotation of the material is used to quickly discharge from the side.
(5) The characteristics of the dust removal device, the dust carried by the exhaust air is effectively intercepted by the cloth bag, and the dust removal is completed by the blast. At the same time, the dust is blasted into the hot air to avoid moisture clogging of the filter. In addition, the strong hot air blows back dust and cleans the dust.
2.3.3 Views on the manufacture of fluidized bed coating equipment Compared with the one-step granulator, the domestic fluidized bed coating technology is still in its infancy, mainly because the Wurster system is based on spouted fluidization. In terms of mechanism, the theoretical and experimental research on its mechanism is still not perfect. To improve the manufacture and application of equipment, I have three opinions.
First, the particle diameter, specific gravity and weight-to-weight ratio of the granulated coating materials are quite different. It must be applied reliably to the corresponding granulation coating production, and the coating-distribution area air volume distribution and opening The design of the porosity is the core of its technology. Therefore, it is necessary to have a small model for testing, and also have a test bench for production models. Currently, only about 2 in China have this condition;
Second, the necessary testing equipment, a supporting equipment for the fluidized coating machine needs to be selected, designed and manufactured under the guidance of the data obtained from the small test. Therefore, it should be equipped with a device such as a dissolution apparatus and a violet indexing instrument. ;
Third, the formulation technology, the choice of excipients and the preparation of coating film are the basis of the production of this preparation, and it is also a step in the design of fluidized bed coating machine. There must be relevant research, researchers To understand the craft and understand the equipment, the combination of the two can create a new world of fluidized bed applications.
From the experience of international advanced fluidized coating equipment, companies such as Glatt, Aeromatical and Disonia are equipped with complete experimental equipment, inspection methods and process technicians, and are widely used in the world. The pre-sales service and project cooperation of the pharmaceutical factory can be used for learning and reference in China.
2.4 Analysis of the current situation of fluidized bed pulverization technology and equipment In addition to the above-mentioned applications of fluidized bed technology, fluidized bed has been used in airflow ultrafine pulverization in recent years. In the airflow ultrafine pulverizing machine, the fluidized bed collision type airflow pulverizer is used as shown in Fig. 10. When the material is sent to the pulverizing chamber, the airflow (which may be inert gas or air) enters the fluidized bed through the nozzle. The pulverized particles collide at the intersection of the high-speed jet stream. It is studied in the literature that the point is located at the center of the fluidized bed, and the particles are pulverized by the high-speed impact of the airflow on the particles and the collision between the particles, and the wear is not affected by the wall. Almost no wear and tear. Among them, the structure of the fluidized bed collision type jet mill is almost no wear or small to the wall surface, and the medium passing through the nozzle has only the air flow and does not enter the crushing chamber in the same way as the material, thereby avoiding the impact of the particles on the way. Friction and adherent deposition also avoids particle wear on pipes and nozzles.
The fluidized bed technology runs through the entire process of airflow pulverization, including material transport, grading and collection. From the pharmaceutical industry application, fluidized bed airflow pulverization is the perfect machine in the airflow crushing family, mainly due to the almost wear-free nature of the pulverization process, which fundamentally solves the application of the pulverizing equipment in the raw material medicine, especially It is applied on aseptic preparation, which solves the "four" problems, that is, the control of oxidative or heat sensitive; the second is the control of pulverization fineness; the third is the control of insoluble particles; the fourth is the equipment can be effectively cleaned and sterilized .
2.5 Current status analysis of fluidized bed mixing technology Based on fluidized bed mixing technology, it is mixed into other equipment types, and no special analysis is made here. The main point is that the multiple components are clustered, the separation and interleaving are frequent and sharp, and the mixing time is short, except for the disparity in specific gravity.

Discussion on the development prospect of 3 fluidized bed technology and equipment in pharmaceutical industry

3.1 Prospects for explosion-proof safety Domestically developed explosion-proof safety fluidized bed equipment has only been manufactured by very few manufacturers. With the in-depth implementation of domestic GMP and the emergence of new dosage forms, more organic coal will be involved, flammable and explosive. The application of materials in fluidized bed equipment not only involves the explosion-proof nature of its own materials, but also involves electrostatic and dust explosion problems. Therefore, the development of explosion-proof safe fluidized bed equipment has great market potential.
3.2 Prospects for cooperative development The formation of any equipment depends on the technology of the process test, and the development of new equipment will drive the transformation of new dosage forms and new processes. At present, the development of new dosage forms is a commonly used method in the pharmaceutical industry in developing countries. The development and industrial application of slow-release pellets must be organically combined with pharmaceutical companies and pharmaceutical companies to achieve a combination of the two and complementary process equipment. And technology sharing, which has good prospects.
3.3 Prospects for process equipment development Fluidized bed technology has made revolutionary progress in the 1950s, in which the * revolution was a one-step granulator produced by the combination of the technology and the spray technology by the engineers of the hills; the second revolution It is the bottom spray coating column established by Dr. Wurster, and the eddy current drive fluidization developed by German HUTTLIN company is pushed into the third revolution. The use of eddy current driving to produce rotary fluidization, in fact, the combination of the advantages of top spray, bottom spray and cut spray, its characteristics: First, regular flow fluidization, to achieve a slow release coating; second, spray can be unlimited, The coating time is short and the operation is fast; the third is the convection of large air volume, the drying speed is fast, and the fourth is the swirling fluidization, which can produce pellets with high sphericity and large specific gravity particles.
From this point of view, the fourth revolution is particularly important. It will be based on a variety of technologies, low energy consumption, high efficiency and speed, and more in line with the various points of GMP regulations, which is of great significance. In terms of fast and efficient, the author believes that the fluidized bed belongs to a uniform bed, the material temperature gradient is small, that is, the full mixed fluidization, the material is randomly moving, so it is not suitable for slow release coating. The German Glatt company has matured its coating technology by top spray. Due to high-strength convection drying and no restrictions on spraying, it is an ideal and efficient method, but it should solve the following technical problems: 1 cross-section wind speed gradient; The mist particles are bonded to the material by coating without causing bridging granulation; 3 the coating film is dried or lost prematurely; 4 fluidized ordered movement.同行只要能悟出其要求,迎刃而解的话,新的流态化技术在制药工业应用前景会更广。
4小结本文从流化床的基本概念入手,分析和比较了流化床在制药工业应用的现状,也阐述了几种流化床设备的特点,同时,对流化床技术的发展和应用前景作了探讨。笔者抛砖引玉地陈述,使人们正视目前流化床技术及设备应用的现状,更好地把各自流化床设备升级换代,把流态化这一经典的技术发扬光大,使流态化性能会延伸出更多的应用。同时推动国内流化床技术及设备能赶超世界先进水平。

[参考文献]
[1] 金国淼等,干燥设备,化学工业出版社,2002
[2] 邹龙贵,微丸制剂及缓控释包衣的制备与设备的应用,中国制药装备杂志,2005/2
[3] 田耀华,制药装备符合GMP要求的设计和选型要点(三),中国制药装备行业协会,2003
[4] Glatt公司,流化床颗粒包衣制丸工艺,制药装备实施新技术新产品信息文集,中国制药装备行业协会,2001
[5] 李凤生,超细粉体技术,国防工业出版社,2001■

作者:邹龙贵信息来源:中国制药装备专辑第13期

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