How To Optimize The Fluidized Bed Process (Chapter 3)

Key Points Of This Chapter

Only at the beginning of this chapter do we really get into the interpretation of fluidized bed hardware. The design of hardware is based on process requirements. Everyone must firmly believe in this. No piece of equipment can satisfy all types of certain processes. There must be an optimal space for this. Space is our understanding of craftsmanship.

According to the textbook, the pharmaceutical fluidized bed has four major functions: drying, top spray granulation, bottom spray coating, and side spray pill making. However, in the process of implementation and application, everyone found that the side spray pill making function is in reality. There are fewer and fewer applications, because there are independent centrifugal granulation/pellet making machines, which are simpler to operate, have greater capacity and faster than the side spray function in the fluidized bed, while the fluidized bed side spray has developed into a Unexpected coating function (powder coating technology).

This chapter mentioned the following words many times: physical and chemical properties, flow characteristics, fluidization characteristics, URS, AHU, collection bag, filter, etc. Through these high-frequency words, we found that fluidized bed hardware is a systematic project In addition to the fluidization chamber, there are also AHUs, capture/filtration and other devices. Special attention should be paid to the temperature and humidity of the inlet air. The application of fluidized bed is also a systematic process engineering. It is necessary to clarify the quality requirements of the final product and the raw and auxiliary materials. Comprehensive evaluation of cooking properties, fluidity, fluidization, solubility, etc. can ensure the rationality and stability of process design.

The Components And Functions Of The Fluidized Bed System

01 Introduction

As mentioned in the previous chapter, understanding the process equipment will assist in designing the process and thus enable the optimization of the fluidized bed process. Fluidized bed equipment is typically installed in a Good Manufacturing Practice (GMP) area, while ancillary systems such as air handling units (AHUs), ductwork, exhaust fans or blowers are located in the general area behind the processor unit, or Located on a mezzanine or outside the building. Understand the function of each component of the fluidized bed system and the requirements of your process, then select and install the equipment accordingly.

Fluidized bed systems vary in functionality and purpose. Due to the processor’s versatility, it is often referred to as a “multi-unit processor”. Use different modules for different unit operations such as drying, granulation, granule coating, pellet coating, melt granulation, taste masking, etc.

Selecting a fluidized bed processor requires several aspects of knowledge. In the early stages of product development, the choice of fluidized bed technology is determined based on the results of laboratory trials. Based on the initial process development, we must evaluate the equipment requirements for pilot scale and ultimately achieve commercial production of the product.

Scale-up issues and material handling should be carefully considered when considering commercial-scale units. Ultimately, process optimization is how to execute commercial production with the least amount of labor and time.

It is recommended to communicate with the equipment manufacturer and establish a User Requirements List (URS) based on your process. Equipment vendors and engineering staff in your engineering department can indicate the need for utility, installation, and other support services. If you are not familiar with this technology, it is necessary to visit some pharmaceutical manufacturing companies that use fluidized beds. Listed below are some frequently asked questions. (These problems do not represent common problems for all products, because different products and processes may have unique problems and solutions).

02 Issues To Consider Before Choosing Equipment

(1) URS Can Be Prepared Based On The Following Questions

• What are the specifications of production/pilot fluidized bed equipment?

• What unit operation do you want to use the fluidized bed for? (e.g., drying, granulating, coating)

• What is the product that needs to be processed? Is the product 100% API, or is it composed of API and other excipients?

• What are the physical and chemical properties of API and excipients?

• What are the density, moisture content and flow characteristics of API and excipients?

• What are the product characteristics of a mixture of API and excipients?

• What are the physical and chemical properties of excipients?

• What is the ratio of API to excipients?

• What is the solubility of API and excipients?

• Is it a highly active drug? What is the active class? Are special environmental controls necessary? Is a glove box required for operation?

• How expensive are APIs?

• Whether the material is toxic, flammable, corrosive or abrasive (ps. The particles have high hardness and density.

• Is the material toxic, flammable, corrosive or abrasive (ps. The particles have high hardness and density, causing the contact parts to be damaged by grinding)?

• What is the final granulated particle size distribution?

• What are the post-fluidized bed processing steps? Is the final product just granules, or is it mixed with other ingredients for further processing or packaging?

• Is the coating used for modified release applications, or is it compressed into tablets and filled into capsules? In short, what is the final process for the product?

• How big is the factory space? What are the factory air temperature, humidity, and cleanliness requirements? What gas/steam sources and power sources are needed?

• Where will it be installed?

(2) Fluidized Bed Granulation

• If granulating in a fluidized bed, what binder will be used? Is the binder added after being dissolved/dispersed, or is it added as a dry binder? What is the concentration and viscosity of the binder solution? Can it be pumped? Is the adhesive delivery completed? What is a solvent (is it a water-organic solvent or a mixture of organic solvent and water?)

• What are the fluidization characteristics of the product to be granulated?

• Do materials need to be processed in batches or continuously?

• Is it necessary to control the humidity of the inlet air? (This is usually strongly recommended to ensure the consistency of process parameters)

• What is the batch size, and what are the current process requirements and final product requirements?

(3) Fluidized Bed Drying

• If you only dry the particles, please confirm how to transfer the wet material to the fluidized bed. Is it manual transfer or equipment automatic transfer?

• What is the viscosity of the wet material? What is the moisture/solvent content of the wet material?

• Is the wet material very sticky? Is it easy to fluidize without other assistance? Do we need mechanical agglomeration to promote fluidization?

• When drying granulated materials, if the solvent of the binder is water (ps. This is mainly based on EHS considerations and is a low risk). It can be discharged from a high shear wet granulator or simply “dumped” into a fluidized bed to be dry exploded.

• If it contains organic solvent, the wet material can be vacuum pumped to the running fluidized bed. (ps. Since the operating fluidized bed is under negative pressure, it acts like a vacuum cleaner to evacuate the fluidized bed from a high shear wet granulator or through other integrated systems. Although this is not part of the actual fluidization, But infeed and outfeed are essential to the safe operation of the machine and, if not taken into consideration, may affect product quality, batch yield and integrity).

• If the wet material contains organic solvents, does it need to be gradually transferred during the dry explosion process to avoid exceeding the lower explosion limit (ps. In the overall transfer, the organic solvent concentration may be too high and reach the lower explosion limit)?

• The moisture of the material is bound water (chemically bonded inside the particles) and unbound water (also called free water) [ps. Bound water: It is combined with the main body through chemical bonds, that is, primary valence bonds (often coordination bonds), and is difficult to It reflects the nature of water and is more difficult to remove; crystal water: often combined with the main body (usually salt) through hydrogen bonding, and there are other bonding methods, which can often be removed after heating or other simple chemical methods; free water: with Is the main body physically bonded, that is, a secondary bond (such as van der Waals force), and can it be removed by dry blasting agents or physical means, or a combination of both? What is the initial and final moisture content of the material? The maximum allowed for the material What are the dry explosion temperatures and possible dry explosion times?

• Final product quality requirements: Will the material shrink, degrade, overdry, or become contaminated during the drying process? What uniform level must its final moisture content maintain? What should be the temperature and bulk density of the final product? High shear Do the capacity of the wet shear granulator and the capacity of the fluidized bed have to be the same? Or is it possible to use multiple sub-batches for a dry explosion cycle? (ps. So the capacity of the granulator will determine the amount of product that needs to be dried and therefore the Size of fluidized bed unit required.

• Is the equipment dedicated to one product?

(4) Fluidized Bed Coating

• What is the particle size of the carrier to be coated?

• What is the coating solvent?

• Is it just functional coating? Or is it solution/mixed liquid coating?

• Batch size and effective capacity of coating cavity?

03 Components Of Fluidized Bed Processor

(1) Fluidization Cavity

The fluidization chamber is composed of a pipeline system, which introduces the processed air from the lower pressurized chamber, passes through the loading chamber and material layer, then passes through the expansion chamber and collection chamber, and finally discharges the dry moisture.

(2) Air handling Unit (AHU)

Using AHU can achieve filtration, heating, cooling and dehumidification effects. Air dehumidification is particularly important when the production unit is located in a climate with large changes in humidity, since the evaporation rate of the adhesive liquid is determined by the heat and mass transfer process. If necessary, humidification is usually accomplished by adding clean steam after a heating or cooling phase, and the outside air is filtered and cooled via a direct expansion coil (refrigerant coil) or a cooling fluid coil (ps. Direct expansion coil (direct expansion coil) is An important component used in refrigeration systems, usually used in air conditioning and refrigeration equipment. It is a coiled component made of metal tubes filled with refrigerant (also called refrigerant).

The direct expansion coil realizes heat transfer and temperature regulation by contacting the surrounding air or liquid; the refrigerant coil is an important component in the air conditioning or refrigeration system, used to transmit and transfer refrigerant. It is usually a spiral metal tube that absorbs or releases heat through the refrigerant flowing inside it to cool or heat the air. The refrigerant completes the heat transfer inside the refrigerant coil through the cycle of condensation and evaporation. Refrigerant coils are usually installed inside air conditioning units or refrigeration equipment and used in conjunction with fans or air circulation systems to regulate indoor temperatures). Cooling coils are also used for air dehumidification. Condensation occurs when moist air passes across the surface of the coil that is being cooled. Typically, the lowest dew point achieved with surface cooling dehumidification is +36°F (+2°C).

If drier air is needed, use a rotary dehumidifier. The air passes through the adsorbent material (silica gel or alumina) in the rotating wheel, and part of the rotating wheel is regenerated by blowback of heated air. Injection of dry steam can also be used to control humidity within required accuracy. Heating components are used to heat process air to specified conditions. Finally, the process air is filtered through HEPA (High Efficiency Filter) to provide purified process air required by GMP.

(3) Air Intake/Exhaust Unit

The exhaust fan is located at the downstream end of the unit and generates suction to draw air out of the air handling unit and make the pressure in the cavity lower than the surrounding pressure. The air will passively pass through the exhaust filter, reach the fan impeller and be discharged. If a solvent is introduced, a catalytic oxidizer will be installed to absorb the solvent and achieve purification.

The air flowing out of the fluidized bed is usually filtered again after the capture chamber to prevent contamination of the environment. This structure may include:

•Dust collector

•Water washing dust removal or incinerator (thermal oxidizer)

• Safety filter with bag-in-bag-out (BIBO) structure for high-level exposure protection (ps. Bag-in-bag-out safety filter BIBO: In specific applications such as industrial production or experimental laboratories, infectious disease rooms, etc., there is a The demand is to treat the emission of waste gas, and this type of waste gas is quite dangerous. When dealing with the collection of hazardous waste gas, this type of BIBO bag-in-bag-out filter will be used. It cannot control the waste gas itself and can only pass through The filter collects hazardous waste gas, and this collection process will not cause leakage. Staff who maintain and replace the filter will not be in direct contact with the waste gas. The installation and replacement of the filter will be isolated by bags and replaced. The filter is handed over to a specialized hazardous solid waste treatment department for processing. As shown below, the picture comes from the Internet).

• Closed loop recovery systems (designed to recover and/or capture liquids and products for disposal or possible reuse).

(4) Loading Cavity/Pot

The loading chamber/pot is mainly used to store materials to be processed. The process air is controlled by the air inlet valve and evenly introduced into the loading chamber/bottom of the pot. If the air is not properly distributed before reaching the bottom of the pot, unstable fluidization will occur. The selection of loading capacity should be no less than 35%-40% and no more than 90% of the volume of the loading cavity/pot. The air flow distributor at the bottom is made of stainless steel and can provide an opening area of 2%-30% (ps. With the development of air flow distributors, from plate distribution to three-dimensional distribution, this value is also changing). Under the rated air volume, the opening area determines the airflow speed. Generally speaking, the air flow distributor should be selected so that the static pressure drop between the material bed and the air flow distributor is 200-300mm water column. Common air distribution plates use 60-325 mesh screens to ensure sufficient strength and prevent material from leaking into the air inlet channel. Cleaning is a big challenge due to screen clamping. Therefore, in order to solve the cleaning problem and ensure strength to facilitate hardware processing, some equipment manufacturers have launched air flow distributors without screens.

(5) Atomized Liquid Spray Unit

There are several types of atomizing spray guns used for fluidized bed granulation/coating. The binary spray gun system is the most popular because of its ability to operate at very slow liquid flow rates and the droplet size can be controlled independently of the flow rate. A binary spray gun is used in which the adhesive liquid is pumped into the liquid path and atomizing air breaks up the liquid stream into fine droplets. The higher the pressure, the finer the droplets. Single-head spray guns are typically suitable for trial scale in 100kg batches. Depending on the size, a three-head spray gun, or a multi-head spray gun can provide greater spray volume.

In terms of solution delivery, a peristaltic pump is typically used to deliver the adhesive solution to the nozzle. One pump per gun is highly recommended.

An oil-free and water-free compressed air source that can display the volume and an atomization pressure gauge (indicator) are also needed to atomize the liquid.

(6) Public Facilities

The utilities and space involved need to be discussed before purchasing equipment. Obviously, the equipment and ancillary equipment, which is a fraction of the actual equipment size for this massive project, must be able to be installed in the planned building facilities.

(7) Capture Unit

During the granulation or drying process, mechanical shaking is used to remove adhering materials in the collection bag, while the cartridge filter achieves the same purpose through compressed air backflushing.

Catching bags are made of polyester, nylon or polytetrafluoroethylene (PTFE). Typically, suppliers will provide capture bags made of polyester or nylon material with conductive threads embedded in them. The filter pore size is usually about 20μm, unless your product requires a smaller micron filter pore size, and the system has the ability (mainly fan capacity) to overcome the pressure resistance caused by the smaller filter pore size. Collection bags with a pore size of 1 μm are also useful. The selection of the type of collection bag and its filtration accuracy is very critical. If the fluidized bed is used exclusively for drying, a single filter bag (see Figure 3.4 a) should be sufficient and cheaper. However, keep in mind that this may have an impact on the consistency of drying times and the resulting dry particle size distribution, since each time the bag is shaken, the bed will collapse at the moment of shaking. Therefore, it is necessary to choose a double-chamber separate collection bag. These separate catch bags can be shaken alternately without interrupting the process.

Cartridge filters use one or more cylindrical cartridges located within a housing. The air with particles is directed to the outer surface, and then the exhaust gas flows through the hollow center of the barrel and out, while the particles are captured. The media used in these filters is pleated to increase surface area, often with multiple concentrically pleated sheets wrapped around a central core. The sheets can be made from any thin material that can be folded without breaking, including cellulose, polyester, fiberglass, polytetrafluoroethylene and polyethersulfone.

In the case of highly active pharmaceuticals, installation of stainless steel filters should be considered. This is only justified if you have a high-value, high-activity product and operator exposure to the compound is considered hazardous. The cost of stainless steel filters is very high. However, unlike catch bags or other cartridge filters, the stainless steel filter element can be cleaned in place, making cleaning verification easy.

For functional coating of granules or pellets that do not require filter shake bags, a filter device can be used.

(8) Control Unit

The fluidized bed granulation process can be controlled by pneumatic analog controls or state-of-the-art programmable logic controllers or computers. The electronic control system not only provides repeatable batches according to the recipe, but also provides complete records and printouts of all process conditions. Process control technology has changed very rapidly and will continue to change as computer technology advances and control system costs decrease. The U.S. FDA’s CFR Part 11 requirements create many methods to ensure that these control systems comply with current regulations.

04 Summary

Understanding process equipment and its capabilities is critical to designing processes and obtaining optimized results. Before equipment is selected and specified, the process should first be fully tested and designed to obtain the desired product attributes. Identification of user needs will assist in procuring the right equipment and ancillary systems.