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Fluidized bed granulation, also known as one-step granulation method, is a method to complete the three steps of mixing, granulation and drying of conventional wet granulation in a closed container at one time. Fluidized bed granulation is a complex process, which is affected by many factors, including equipment factors, process factors, prescription factors, etc. The equipment factor is related to the structure of the granulator, the process factor is closely related to the actual operating conditions, and the prescription factor is related to the type and concentration of the granulating materials and adhesives.
一、Equipment factors
In a fluidized bed granulator, both the air distributor and the container affect the particle movement. The material and shape of the container have a greater impact on particle motion. It is necessary not only to ensure that the material powder can reach a good fluidization state, but also to ensure that the material does not adhere to the container wall, otherwise a large amount of fine powder will be produced during the granulation process.
At present, containers are made of a variety of materials, mainly stainless steel with low carbon content (sus304), and the shape is basically a cylinder or cone with narrow bottom and wide top. Most manufacturers of fluidized beds have adopted polishing treatment for the cylinder. During the granulation process, one or two layers (about 180 mesh) of stainless steel screen will be placed on the air distributor, which not only plays the role of carrying materials, but also weakens the influence of the air distributor on particle movement to a certain extent. Even early foreign literature reported that the air splitter had no effect on particle motion.
When using a top spray fluidized bed, the position of the nozzle will affect the uniformity of spray and the wettability of the material. In order to make the particle size distribution as narrow as possible, the spray area should be adjusted as large as the wet bed surface area. If the position is too high, the distance from the nozzle to the material is longer, which increases the volatilization of the liquid medium, so that the material cannot be completely wetted, and the fine powder in the particles increases, presenting a spray drying phenomenon. The nozzle position is too low, the adhesive can not fully contact with the material after atomization, the particle size is uneven, and the nozzle leading edge is prone to spray obstacles.
The structure of the mixer will also have a great impact on the granulation when the rotating jet fluidized bed is used for granulation. Foreign reports have compared the effects of two mixers with different impeller shapes on granulation. Under the same conditions, the reference mixer causes many wet materials to adhere to the wall, while the other mixer does not.
In addition, the type of spray gun (single air flow, double air flow, high-speed flywheel, high-pressure airless spray gun, etc.) and the material of filter bag also have a certain impact on the particle quality.
二、Process factors
1.Inlet temperature
The inlet temperature should be controlled within an appropriate range. If the solvent of the adhesive is water during granulation, according to the nature of the material and the required particle size, the inlet temperature is generally set in the range of 25-55 ℃. It has been proved by experiments that when the inlet temperature of the same material rises from 25 ℃ to 55 ℃, the resulting particle size decreases from 450um to 240um.
If the solvent of the adhesive is organic solvent such as ethanol, the inlet temperature should be slightly lower, generally within the range of 25-40 ℃. If the temperature is too low, the solvent can not be volatilized in time, which makes the powder excessively wet. Some material powder will adhere to the wall of the vessel and cannot fluidize, which is easy to cause adhesion between particles and agglomeration. If the temperature is too high and the intake temperature is too high, the adhesive droplets will be dried too early to effectively granulate, and the properties of some temperature-sensitive materials may also be changed. When drying, the inlet temperature is generally set at about 60 ℃. If the temperature is too high, the solvent on the particle surface will evaporate too quickly, which will prevent the inner layer from diffusing outward, resulting in a large number of particles that are dry outside and wet inside. If the temperature is too low and the drying time is too long, a lot of fine powder will be produced.
2.Fluidized air volume
Fluidized air volume refers to the amount of air entering the container, which should be at a value that makes the material in an ideal fluidized state. In the process of slurry granulation, if the air volume is appropriate, the material is in a good fluidization state, and the heat exchange is in a balanced state, which is conducive to granulation. If the air volume is too large, the moisture of the adhesive volatilizes too fast, the adhesive force is weakened, and the adhesive droplet can not fully contact with the material, so that the particle size distribution is wide, and there are many fine powders. When the air volume is too low, the solvent in the adhesive can not be volatilized in time, and the fine powder of the material is excessively adhered. If the air volume is not increased in time, large particles with large particle size will appear, which will form a large lump, resulting in bed collapse, This is a serious accident in industrial production.
In the granulation process, the filter bag sometimes adsorbs a lot of material powder, resulting in the reduction of the actual fluidization air volume, so the fluidization air volume should be appropriately increased.
3.Atomizing air pressure
The role of atomizing air is to make the adhesive solution form droplets. The particle size of the droplets is directly related to the particle size of the prepared particles. It is believed that the greater the atomizing air pressure, the smaller and more uniform the particle size of the obtained droplets, and the smaller the particle size of the prepared particles. When the spray pressure is too low, on the one hand, the atomized droplets will increase, on the other hand, the atomized droplets' spray cone angle will decrease, and the range of wetting powder particles will shrink, resulting in uneven distribution of atomized droplets, which is easy to produce large wet blocks in local areas. Because the fluidization state of materials will be affected by both fluidization air and atomization air, the pressure of atomization air will also have a great impact on the fluidization state of materials. When the atomization air pressure is increased, the fluidization state of materials will be weakened, and the fluidization air volume should be increased; On the contrary, comprehensive consideration should be taken in operation.
4.Flow rate of adhesive
The flow rate of the adhesive and the temperature of the inlet air determine the humidity in the granulator. When the inlet temperature is constant, increasing the flow rate of the adhesive will increase the droplet size of the adhesive and the humidity in the granulator. The wet particles cannot be dried and agglomerated in time, which is easy to cause bed collapse. Under the same conditions, when the flow rate of the adhesive is too low, the particle size is small and the fine powder is large, which not only prolongs the operation time, but also easily blocks the nozzle.
If necessary, the flow rate should be controlled according to the viscosity of the adhesive solution. If the viscosity of the adhesive is too large, the flow rate of the adhesive can be appropriately reduced, but the inlet temperature should be increased, otherwise it is easy to cause nozzle blockage and bed collapse. When the viscosity of the adhesive is low, the flow rate should be higher.
三、Prescription factors
1.Nature of material
In fluidized bed granulation, particle size and particle size distribution are important physical properties of materials. The smaller the particle size of the material powder, the larger the surface area of the material, and the larger the amount of adhesive required. It has been reported in foreign countries that the smaller the particle size of the material powder, the smaller the particles prepared under the condition of constant adhesive flow rate. When the particle size of the material powder becomes smaller, the flow rate of the adhesive should be increased to produce the same particles. However, the particle size of the material powder should not be too small, otherwise the particles are easy to produce adhesion, which is not suitable for fluidized bed granulation. The particle size distribution of the material is wide, the prepared particles are firm and the porosity is low; On the contrary, the prepared particles are loose and have high porosity.
When granulating with hydrophilic materials, the powder and adhesive are miscible and easy to agglomerate, so fluidized bed granulation is suitable. However, the powder particles of hydrophobic materials can be bonded together by the bridging action of the adhesive, and form particles after the solvent evaporates. No matter hydrophilic or hydrophobic materials, the particle size of the powder should not be greater than 280um, otherwise the prepared particles have color spots or the particle size is too large, and the distribution is uneven, thus affecting the dissolution and absorption of the drug. The granulation effect can be improved by premixing raw and auxiliary materials outside the machine before feeding.
When the material is water absorbent, such as starch, the water absorption of the material will make the powder surface not completely wet, so the flow rate of the adhesive should be increased. Even if the same material has different water content, the flow rate of the adhesive should not be the same. Under the same conditions of the flow rate of the adhesive, the larger the water content of the material, the larger the particles produced. When the material is hydrophobic and not easy to wet, it is not easy to granulate, and the prepared particles are small. You can try to use other solvents or add surfactants to the adhesive solution to improve.
The amount of material also has a great impact on granulation. When the dosage increases, in order to fluidize the material, it is necessary to increase the air inlet. At the same time, the probability of the material being wetted decreases, and the liquid injection rate should be adjusted accordingly. However, if the material quantity is too large, the material powder is not easy to reach the fluidization state, and it is easy to block the nozzle and filter bag, resulting in the reduction of fluidization air volume and affecting granulation.
2.Selection of adhesive
The function of the adhesive is to form a solid bridge between the powders. The type, concentration and adding method of the adhesive have a great influence on the granulation. The selection of adhesive is the key of the whole fluidized bed granulation process. The ideal adhesive should have good affinity with the surface of the material powder to facilitate wetting and mutual bonding to form particles. Gaojie and others use different adhesives for fluidized bed granulation, and the resulting particles are very different in porosity and compressibility. The recommended adhesives are mainly PVP, CMC, MC, CAP, HPc, gum arabic, peach gum, starch, etc. They can also be used together to achieve good results.
When the viscosity of the adhesive is high, the binding force of the liquid bridge formed is relatively strong, and it has the ability to form secondary and tertiary condensation granulation processes between particles, fine particles and particles, so the particles produced are also large. However, if the concentration is too high and PVP aqueous solution with a mass fraction of 10% is used as the adhesive, it is not only easy to block the nozzle, but also easy to cause bed collapse. When the concentration is low, the adhesive force between particles is not enough, the prepared particles are small, and many fine powders are produced during the drying process, which can not achieve the expected effect. Sometimes, the particles made from the alcohol solution of the adhesive are small and there are many fine powders. You can add an appropriate amount of water to the adhesive solution to improve the viscosity of the adhesive, which can significantly improve the quality of the particles made.
The addition methods of adhesive include external addition, internal addition and internal and external combination. In most cases, the first two methods are needed. When the internal addition method is used for the same adhesive, it is not easy to cause the viscosity of the adhesive due to the rapid volatilization of the solvent, and it is not easy to make particles or make smaller particles. When the viscosity of adhesives such as Sanda (partially pregelatinized corn starch) produced by Kalekan Company is particularly easy to induce, the internal addition method can be used, for example, to prepare the specification of 500mg capsule paracetamol tablets. As long as the use of paracetamol with a mass fraction of 85% and sanda with a mass fraction of Qiao%, the core can achieve good hardness and less than 0.19% fragility. However, when the amount of adhesive is small, the internal addition method should not be used.
Problems that should be paid attention to in actual production
In actual production, sometimes the problem of agglomeration or bed collapse may occur, which may be caused by the excessive flow rate and concentration of the adhesive and the wet particles sticking together before drying, or the excessive relative humidity in the fluidized bed granulator, which exceeds the critical relative humidity of the particles themselves. The flow rate of the binder can be reduced, and water or ethanol can be added to reduce the viscosity. At the same time, the fluidizing air volume should be appropriately increased and the inlet temperature should be increased.
At the beginning of granulation, because the temperature of the material is not completely consistent with the temperature of the fluidized air, the solvent of the adhesive cannot be completely volatilized, so the flow rate of the adhesive should not be too fast, and the atomization pressure should be appropriately increased. After the temperature of the material is consistent with the temperature of the fluidized air, the flow rate of the adhesive should be appropriately increased and the atomization pressure should be reduced.
The raw materials of traditional Chinese medicine granules are basically raw powder and extract, usually without fillers. When fluidized bed is used to prepare traditional Chinese medicine particles, if common adhesives are selected, the preparation of particles can not be completed by this granulation technology alone. It is necessary to cooperate with the old process in some processes. Therefore, to truly achieve one-step preparation of traditional Chinese medicine granules in fluidized bed, it is advisable to directly replace the adhesive with the extract. The extract is an adhesive, and the particle color and the content of active ingredients will vary with the yield of the extract. The particle structure is loose, and the anti-rubbing property is poor. It is not ideal to be directly used as a finished product. However, the quality of the tablet is significantly improved when used for tablet pressing. The surface of the tablet is highly smooth, which fully meets the requirements of sugar coating and film coating. When preparing granules with the extract, the humidity of the environment, especially the humidity of the fluidized air, should be controlled because the extract product is easy to absorb moisture.
In order to ensure the quality of drugs, the fluidized bed granulation process must not pollute the production environment or drugs.
The hot air entering the system for fluidization and drying must be heated first and then filtered by medium-efficiency and sub-high-efficiency filters. Dehumidification is also required if necessary to ensure that the gas used is dry and clean and does not pollute drugs. Before the compressed air source required by the system enters the fluidized bed, a series of measures such as dehumidification, deodorization and dust removal shall also be taken.
The fluidized bed must be cleaned regularly and thoroughly during production and use, especially when changing drug varieties, so as to prevent drug cross contamination, batch mixing and drug mixing. The filter bag is generally made of anti-static cloth, which should be carefully cleaned after each granulation. On the one hand, it is a hygienic requirement. More importantly, once the filter bag is blocked, it will not only cause a sharp reduction in the fluidization air volume, seriously affect the fluidization state of the material, but also increase the dust in the bed, and the granulation process cannot be carried out smoothly. When preparing granules for capsule filling and dense spherical granules for coating, the rotating fluidized bed granulation should be the main method.