How To Optimize The Fluidized Bed Process (Chapter 1)

In addition to drying, fluidized bed applications are already mature with granulation, coating and pill making functions. However, with the deepening of fluidized bed research, more subdivided applications have been developed, such as: melt granulation, Melt coating, micron powder coating, vibration pulse granulation, etc.

Fluidized bed is a typical three-state fluidization device of solid, liquid and gas. The structural design affects the distribution and residence time of the three states, which leads to the complexity of the process. Therefore, pharmaceutical fluidization is still a semi-blind box state. , there is an urgent need for one or more means to visualize and digitize the fluidization state, so as to lay the foundation for true research on pharmaceutical fluidization.

Part 1 Introduction

1 Introduction

The fluidized bed granulation process is a mature unit operation in the pharmaceutical industry; in other fields, such as food, nutrition, agrochemicals, dyes and other chemical industries, it is used to solve particle agglomeration, dust prevention, and material cost-effective processing And particle modification and other issues, the purpose is to improve the fluidity, dispersion or solubility of the product.

Earlier, fluidized beds were used as a more efficient drying device compared to other methods of drying products. With the emergence of new technologies and drug delivery technologies, in addition to drying functions, fluidized beds are often used for granulation, coating and pill making, using melt aggregation to produce granules or modify the release of granules/pellets. Due to its versatility, these units are often classified as multi-processor fluidized bed units.

Fluidized beds have been used for the continuous production of drying and granulating certain large-volume products. In the subsequent chapters of this book, an attempt is made to help the reader address the challenges faced in the daily use of fluidized bed processes.

Fluidization is a unit operation that converts fine solids into a fluid-like state through contact with a gas (usually the process gas is air). At a certain gas velocity, the gas will support the particles, allowing them to move freely without being entrained. This fluidized bed resembles a vigorously boiling fluid, with solid particles experiencing extremely turbulent motions that increase as the gas velocity increases. Smooth fluidization of gas-solid particles is the result of a balance of fluid dynamics, gravity, and interparticle forces. The minimum fluidizing velocity of the air flow depends on particle size, density, shape and even surface properties.

Suspension and movement in the airflow maximizes particle surface exposure to air or gas, producing efficient evaporation. The main factor affecting the fluidized bed process is airflow. In order to understand the process characteristics of fluidized beds, it is important to understand how airflow is generated, regulated and distributed during drying, coalescing and coating processes. We will discuss this issue in the next chapter.

2 Advantages and challenges of fluidized bed

1)Granulation

In the pharmaceutical industry, most solid dosage forms are produced using wet granulation processes. Fluidized bed granulation is an option for improving pharmaceutical powder processing properties such as flowability and tableting.

Fluidized bed granulation can be classified as a single-tank process because the powder can be mixed, granulated and dried in the same unit, facilitating product transfer and minimizing cross-contamination. In addition, the fluidized bed also enhances heat and mass transfer between the fluidizing air and solid particles, resulting in uniform temperature distribution within the product bed and relatively short processing time. Compared to high-shear granulation, fluidized bed technology generally produces particles with a narrower particle size distribution and no oversized particles. This reduces unnecessary multiple granulations and speeds up drying.

Fluidized bed granulation is reported to be more porous, less dense and more compressible than those produced by high shear wet granulation. The optimal particle size range for fluidization is 50 to 2000 μm. The average particle size should be between 50 and 5000 μm to avoid excessive channeling and plug flow. Since fine powder has a very large surface area, the adhesive cohesion increases and leads to aggregation; therefore, in order to avoid excessive escape of fine powder, ultra-dense and inappropriate collection bags are usually selected to cause fluidization imbalance. For fine particles smaller than 50 μm and particles that cannot be fluidized, the powder bed must be treated by mechanical rake and other methods, which increases equipment, cleaning and maintenance costs. The critical size that traditional fluidized beds cannot discretely process ordinary pharmaceutical powders is about 20 μm. According to Geldart’s flow diagram, below this limit, stable flow without any delay is difficult.

Handling powder mixtures containing components of different densities is another challenge, as differences in fluidization behavior of different formulation components can lead to bed separation and uneven mixing. In addition to these powder properties, the ability of binder droplets to spread in the powder bed is also critical during fluidized bed granulation. Therefore, granulation during fluidization is highly dependent on liquid diffusion phenomena. Obviously, fluidized bed granulation is a complex process. In addition to material-related factors such as the nature and characteristics of ingredients in the formula, process factors related to the granulation and drying stages will also affect the results.

2)Dry

Fluidized bed drying consists of three stages: short preheating stage, constant rate stage and falling rate stage. The constant rate phase corresponds to a constant bed temperature. The rapid mixing of the solids brings almost isothermal conditions throughout the fluidized bed, meaning that reliable control of the drying process can be easily achieved. The ability of the air (gas) flow to absorb and carry away moisture determines the drying rate and determines the duration of the drying cycle. Controlling this ability is key to controlling the drying process. Three elements essential to this control are inlet air temperature, dew point and airflow. The higher the temperature of dry air, the greater its saturated water-holding capacity.

3)Coating

Fluidized bed coating offers the possibility to modify and improve various properties of the core particles, such as surface properties in a single unit operation. The challenge with using this technology is the difficulty in selecting the right process conditions to achieve constant coating quality and a stable process, especially during process upgrades. The functions of coatings are wide ranging, from basic necessities to aesthetic purposes. Coatings can be used to improve the chemical and physical properties of the substrate.

4)Challenge

Manufacturing products using the fluidized bed process can present many challenges. Challenges may be related to equipment, material properties, process parameters, material handling, potent compound manufacturing, and process scale-up. The following sections detail the nature and possible solutions to the challenges encountered in each unit operation. As mentioned before, the focus will not be on theoretical aspects but on practical solutions.

Wetting agent volume depends primarily on the solubility of the drug and/or excipients. Insoluble drugs require more wetting agents than soluble drug formulations. Particle size distribution, particle shape, surface roughness, as well as fluid, equipment and process characteristics all influence the wetting dose. Spray and evaporation, these two conditions must be in perfect balance to produce a normal fluidized granulation process (ps. This balance seems simple, but in fact it is difficult to control. The main reason is that the current gas-liquid process in the fluidization process The characterization of the solid three phases and other parameters is fragmented and there is no complete dynamic description. As a result, if the parameters we obtain can effectively correspond to the process and optimize the parameters, it is the difficulty of fluidized bed application); if it exceeds At any of these limits, wetting agent will accumulate in the bed, causing bed collapse or uneven product particles. The adhesive spray rate is one of the key factors in determining the particle size range.

Possible Challenges During Product Processing Using Fluidized Bed Process Technology

• Uneven particle size distribution;

• There are large pieces in the particles;

• Bed stall during granulation process;

• The spray gun is blocked during granulation;

• The spray gun is blocked during coating;

• Poor fluidization uniformity during granulation process;

• Poor fluidization when drying viscous materials;

• The product yield is poor after the process is completed;

• Too many fine particles;

• Poor process air temperature control;

• Uneven distribution of low-dose active pharmaceutical ingredient (API);

• After granulation and drying, the granules are broken;

• Particle agglomeration during coating process;

• High shear particles have clumps after drying;

• The product in the container returns to moisture after drying;

• Local excessive moisture in the granules leads to the formation of large lumps;

• Severe static electricity in materials leads to poor fluidization;

• Safety issues of using organic solvents for granulation;

• The collection bag is clogged;

• Pellets agglomeration during coating process;

• It is difficult to granulate process ingredients;

• The product cannot be enlarged;

• Product transfer in integrated installations creates large chunks;

• Product development is a kind of fluidized bed, and amplification is another kind of fluidized bed;

• As the sticky product is dried, the collection bag becomes clogged;

• Successfully produced in the shear granulation process, but due to high dosage, poor water solubility, low density, and API micronization, the fluidized bed granulation failed;

• The process end points of each batch are inconsistent;

• Lack of optimal endpoint determination tools for granulation, drying and coating;

• Minimize product breakage during drying;

• Transfer tray drying process to fluidized bed drying;

• How to dry organic solvent high shear granulation products without triggering the lower explosion limit threshold?