Through the implementation of the fluidized bed granulation project and the reading of relevant materials, a certain summary of fluidized bed granulation has been made and shared with everyone, hoping to be helpful to everyone. The entire summary is divided into

1. Equipment section

A complete fluidized bed equipment consists of an air treatment unit, material tank, expansion tank, filter bag, spray system (adhesive preparation tank, peristaltic pump, spray gun), and control system. Key parts of the equipment are described

Air processing unit: The air used for fluidized bed granulation must be filtered and dehumidified (humidified). It is particularly important to emphasize the dehumidification (humidification) device. The humidity of the air will have a significant impact on the granulation effect of the fluidized bed. The humidity of the air varies significantly in different seasons. In winter, a dew point of 1 degree is equivalent to 4 grams of water per kilogram of air, while in summer, a dew point of 20 degrees is equivalent to 15 grams of water per kilogram of water. Without humidification or dehumidification equipment, it may lead to poor reproducibility of the process. The lower the dew point temperature, the better. If it is low, the material is prone to static electricity, which can affect the final yield and lead to a lower LOD; Too high a temperature can prolong the drying time. It is generally recommended to control the dew point of the inlet air at around 8-10 degrees Celsius. A dew point temperature of 10 degrees Celsius is equivalent to 8 grams of water per kilogram of air. For materials with a fine powder content *, it can be seen that using a dew point temperature of around 15 degrees Celsius can effectively reduce static electricity and ensure fluidization.

Material tank: It is reasonable for the material to account for 35-90% of the total volume of the material tank. The bulk density of the particles obtained after powder granulation will slightly increase compared to the starting powder, but the difference is not significant. Therefore, as long as the initial feeding amount is within the range of material excess volume, it is sufficient. The aperture ratio of the material tank chassis is very important, as it determines the pressure difference during material fluidization. The aperture ratio is generally 12%, and the aperture of the chassis is generally 100 μ m. Spray gun: After atomization, the liquid diffuses about 1000 times the volume of the solution. The aperture size of the nozzle generally has little effect on the granulation effect. It is recommended to use small-diameter nozzles for solution adhesives, and large-diameter nozzles for suspensions and starch slurries. There are three common types of nozzles: single nozzle type, three nozzle type, and six nozzle type. However, it should be noted that when using multiple nozzle types, the spraying range of each nozzle should not overlap, otherwise it will cause local excess of adhesive. Filter bag: Polyester material is commonly used, with a transmittance of generally 20 μ m and a minimum of 3-5 μ m. Currently, there are also metal filters that use compressed air to flush out the material powder during granulation. Each filter is equipped with a flushing nozzle for online cleaning.

2. Materials section

The main purpose is to introduce the adhesive used in fluidized bed granulation

(1) Starch slurry: In fluidized bed granulation, the concentration of starch slurry is generally recommended to be below 8%. It should be noted that the viscosity of starch slurry varies greatly at different temperatures, so the rate of spraying with a peristaltic pump will also vary. Here is a parameter for reference. It is recommended to stop heating the starch slurry when it is heated to 82-86 degrees Celsius, and maintain the temperature above 60 degrees Celsius throughout the granulation process. If you feel that the viscosity of starch slurry is low, you can use a mixed adhesive, such as 6% starch slurry+3% PVP

(2) Pre gelatinized starch: It can be partially dissolved in cold water, with a recommended concentration of 5-8%. It can also be directly added to the prescription in powder form and granulated with water as a wetting agent. However, compared to liquid form, it requires 2-4 times the amount to achieve the same bonding effect

(3) PVPK30: soluble in water or ethanol, with a concentration range of 5-30%. The commonly used concentration in fluidized beds is 20%. It can also be directly added to powder formulations and granulated with water or ethanol as wetting agents, but the amount required to achieve the same bonding effect needs to be greatly increased. Special attention should be paid to two points when using PVP as an adhesive. Firstly, tablets containing PVP usually harden after storage, making them suitable for effervescent or chewable tablets. Secondly, PVP has strong hygroscopicity. To avoid this, derivatives of PVP such as BASF's VA64 and ISP's S630 can be used, which have the same viscosity as PVPK30 but greatly reduce their hygroscopicity.

(4) PVPK90: The commonly used concentration is 3-5%, and the dissolution rate is slow during preparation. The prepared particles have a large particle size and high hardness, so they are not particularly commonly used.

(5) HPMC: Low viscosity models are commonly used, such as Dow's E3 and E5, and Shin Etsu's Pharmacoat 603 and 606 from Japan. Water or water/ethanol is commonly used as the solvent, with a concentration of 10-15%. If water is used as the solvent, HPMC can be dispersed in hot water at 80-90 degrees Celsius, stirred evenly, and then dissolved in cold water. The water/ethanol mixed solvent can be dispersed in ethanol first, and then diluted and dissolved in water. 3. Process section

The entire granulation process of fluidized bed mainly consists of four steps: material preheating, liquid spraying, drying, and cooling. The descriptions of each process are as follows: (1) Material preheating: In fact, there is also empty machine preheating before material preheating,

The main purposes of preheating an empty machine are twofold:

Firstly, the initial inlet air volume for fluidized bed start-up is generally unstable. By preheating the equipment with an empty fan for a certain period of time, the parameter can be ensured to stabilize, avoiding adverse effects on subsequent material preheating caused by unstable parameters; The second is through machine preheating, which can greatly reduce material preheating time and increase efficiency.

Suggestion for parameter setting during material preheating stage: Due to the high initial material powder rate and static electricity, it is recommended to use a lower inlet air volume while ensuring material fluidization, and to increase the shaking frequency of the fluidized bed as much as possible; Using material temperature as the jump point of the program, the material temperature at the jump point may vary slightly depending on the product properties and production batch, usually between 45-50 degrees. (2) Spray liquid: It is recommended to conduct a spray liquid test before each fluidized bed operation, especially when using an adhesive, and record the spray liquid curve, which corresponds to the spray liquid rate indicated on the peristaltic pump; Observing the atomization state of the adhesive under the set atomization pressure, the judgment standard is: when atomizing the spray, the palm should quickly pass through the entire spray surface perpendicular to the direction of the spray, and there should be no obvious wetness on the palm.

Suggestions for parameter settings during the liquid spraying stage: At the beginning of the liquid spraying stage, the particle size of the material gradually increases from small to large. In order to ensure fluidization, the inlet air volume can be adjusted accordingly (from small to large); The shaking frequency of the filter bag can be set relatively high when spraying liquid, and the shaking frequency and time can be reduced when the material gradually becomes particles. The spraying stage is generally based on time as the jump point. If it is in the process exploration stage, it is recommended to take samples from the fluidized bed sampling port at regular intervals to observe the particle status, especially to prevent the particles from being too wet. In addition, to ensure particle quality and improve production efficiency, it is recommended to divide the entire spraying process into several (usually 2-3) spraying rates for gradient granulation. Regularly record system related parameters (including inlet air volume, inlet air temperature, exhaust air temperature, material temperature, spray rate, atomization pressure, material pressure difference, filter bag pressure difference, filter bag shaking frequency and time, etc.), a good fluidized bed process will have a plateau period at each spray rate gradient, that is, all the above parameters will remain stable. If the parameters of the system keep changing throughout the entire spray state, even if the final prepared particles are good, it does not necessarily mean that your process is superior, especially with poor reproducibility.

(3) Drying: After the spraying is completed, the material is dried at a temperature that is generally not too high, otherwise it may cause over drying. In the process exploration stage, it is generally necessary to take samples when the material temperature reaches a certain level to measure the particle's LOD. When the LOD is within the set range, the drying is completed. If the LOD value that should be reached is unclear, it is generally recommended to reach 1% -1.5% for ordinary tablets. It has also been seen that the LOD of some products is determined. Answer: Possible methods include reducing the air intake volume, increasing the spraying rate, and reducing the atomization pressure. The latter two are more effective, but the prerequisite is to ensure that the adhesive (wetting agent) has a good atomization state.