Challenges and Quality Attributes in Fluidized Bed Processing Method in The Manufacturing of Multiparticulates

Multi-particulate dosage forms are increasingly used for controlled release applications in comparison to single unit dosage forms, mainly because of their therapeutic advantages^1.Among them is the decrease in overall transit times and variance in stomach emptying rates in the GI tract² and the minimization in the peak plasma fluctuation³. Another significant benefit is the decreased chance of adverse effects brought on by dosage dumping. Moreover, spherical particles exhibit several technological advantages such as good flow properties, low friability, while they are perfect for coating due to their low ratio of surface to volume. There are many different techniques for producing pellets⁴ One of the most recent, is Wet granulation is used for pelletization in a fluid bed rotary processor, which is quite interesting since pellets are made, dried, and coated in the same apparatus, eliminating the risks of cross contamination. These are side spray, bottom spray (suitable for Wurster equipment), and top-spray⁵. The final characteristics of the pellets are influenced by a number of variables in this multivariable process. To achieve a controlled process, it is crucial to understand how these variables affect the process. Response surface designs have been extensively used for the characterization and optimization of pharmaceutical processes ^6-7. The spherical shape of the pellets makes them perfect for coating application. Pharmaceutical film coating applications can be selected for both practical and decorative purposes. The purpose of film coating is to change the medication release profile or create a barrier that shields the pellets from the environment. In the pharmaceutical sector, fluidized beds are frequently used to coat solid particles including powders, granules, and pellets. Hot air is used to first fluidize the particles before the suspension or coating solution is sprayed. on top of them. The evaporating solvent and solidifies as a film around the core substance as a result of the hot air. The main difficulty of this process is creating a continuous and uniform film coating on the pellet surface. The intricacy of this coating process, which results from the many variables involved, makes it essential for the pharmaceutical industry to study⁸. For small- particle film coating, the Wurster apparatus ⁹is thought to be the most practical piece of equipment ¹⁰. For particle coating, the fluidized bed is the most effective technique according to Teunou and Poncelet's study on coating in fluidized beds ¹¹. This is reason of agglomeration annular zone's air velocity is lower than that of the inner tube region and the particles are so near to one another ⁷. Each of the aforementioned approaches based on purpose is pellets are manufactured. As a result, during the development process, it is critical to identify major process characteristics that influence product quality^12-14

Challenges

1. Scale-up

Accounting for variations in operational characteristics across units of varying sizes can be challenging when scaling up fluidized bed systems.

2. Temperature control

Temperature management in a fluidized bed reactor can be challenging, particularly when silane is being used.

3.Granulation control

The simultaneous wetting, drying, and mixing of particles makes the granulation process challenging to control.

4.Erosion

 Because fluidized material is solid, it may erode the reactor's internal   components.

5.Initial capital cost

The expansion of the materials in the reactor necessitates an increase in vessel size, which may result in greater initial capital expenses.

6.cGMP compliance

To guarantee its high quality and suitability for use in food and pharmaceutical applications, it is crucial to confirm that the fluidized bed dryer conforms with international standards, such as cGMP.

7.Airflow rate

The viscous resistance of the granules rises with increasing airflow rate, potentially increasing the bed pressure drop. Granulation, coating, and lowering the moisture content of pharmaceutical powders or granules are just a few of the processes that can be carried out with fluid bed equipment. These methods frequently present difficulties, such as increased pellet size, a rougher pellet surface because the coating materials have larger particles, and nozzle blockage that causes uneven layering. When the binder is used in an improper type or concentration, the pellets' surface becomes porous. The pellet's surface smoothness will increase with a higher binder concentration, but the potency will decrease. The weight of the core pellet, the rate at which solution, suspension, or powder is applied, the type of atomizer, Pellet characteristics are influenced by various elements such as location, speed, temperature, atomization, and air cap ^15-17.

Principle of FBD

According to the fluidization principle, particles have a tendency to suspend in the available air and continue in the upward gas stream when a gas is forced through a nozzle faster than the settling velocity of particles or solids. The suspension process is continued when the particles reach the top of the apparatus and are drawn downward by gravity. This process is defined as fluidization of suspended particles ^18.

MECHANISM

1. Nucleation phase

Every time A solvent system is used to moisten the powder, a step in the process of pelletization called the nucleation takes place. The third phase air-water-liquid nuclei system is formed by drawing the primitive particles together and holding them together with pendular liquid bridges. The strength of their binding will increase as size of particle decreases.

2. Coalescence phase

Coalescence is the process by which well-formed nuclei randomly collide to form large particles; it requires a small amount of more moisture on the surface of the nuclei, but the total mass of the system remains constant while the number of nuclei progressively declines.

3. Layered phase

Layering is a technique for progressive development that involves adding fines and fragments                 one after the other to nuclei that have previously formed. The number of particles stays the same during the layering stage, but as the particle size grows over time, the system's overall mass rises. Particle size reduction can create the fragments or small particles. The larger pellets absorb the particles and pieces created during size reduction.

4. Abrasion transfer phase

Abrasion transfer, it involves the transfer of components from one granule to another without preferred in both directions, is the primary mechanism during the ball growth phase. The mass or total number of particles remains unchanged during this phase. However, as long as the circumstances that result in the material transfer persist, the particles experience a constant change in size ²⁵.

Process involved in pellets formation

1. Preparation of Feed Material

The raw materials, often a powder or granule, are prepared. This may involve grinding, mixing, or pre-conditioning to achieve the desired particle size and properties.

2. Fluidization

The feed material is introduced into the fluidized bed, where air or gas is blown upward through the bed. This creates a fluid-like state, allowing particles to move freely and evenly distribute.

3. Nucleation

Initial pellet formation occurs as particles collide and adhere to each other. The process is facilitated by moisture or binder added to promote agglomeration.

4. Growth

As fluidization continues, additional particles adhere to the growing pellets, increasing their size. This growth phase is critical for achieving the desired pellet dimensions.

5. Drying

The moisture content is reduced to stabilize the pellets. This can be done simultaneously during the fluidization process or in a separate drying phase.

6. Cooling

Once pellets reach the desired size and moisture level, they are cooled to maintain their integrity and prepare them for handling.

7. Classification and Screening

The final pellets are classified based on size and quality. Oversized or undersized pellets may be recycled back into the process.

8. Packaging

The finished pellets are packaged for storage or distribution.

Types of FBD²⁰

1. Top spray

The food, feed, and chemical industries commonly use this processing option because the film's primary purpose is to enhance time-limited protection against light, oxygen, and moisture during general handling or storage. For this function, a perfect film is usually not necessary, but in order to maintain good spreadability, care to be taken to before the droplets come into contact with the substrate, make sure they don't get too viscous.

2. Bottom spray coating (Wurster Coating)

When a regulated release of active ingredients is necessary, this procedure is employed. By using less coating material, the Wurster coating process completely seals the surface. When the spray nozzle is placed into the base plate, a spray pattern is produced simultaneously with the air feed. The particles to be coated are fed through the spray cone while being accelerated in the wurster tube using a base plate with various perforations and a wurster cylinder. The particles dry as they ascend and return to the base plate outside the wurster tube. They are directed from the exterior back into the tube's interior, where the spray accelerates them once more to create an extremely even layer off.

3. Bottom Spray Coating (Continuous Fluid Bed)

This method works effectively for protective or colored coatings when the product rates are higher. After the product is continually fed into one side of the machine, air flow propels it forward through the sieve bottom. The system is separated into pre-heating, spray, and drying zones based on the application. In the later, coating liquid is sprayed from below as a bottom

spray. Continuous extraction is used to remove the coated and dry particles.

Fig .1. Fluidised bed with a Wurster insert

4. Tangential spray

The physical principles of this processing method are very similar to those of bottom-spraying coating; the only difference is that a motor-driven rotor disc provides the production motion. Otherwise, the same parameters are used to produce quality. The particles rolling motion prevents agglomeration by providing an even greater separation force. However, coating very small particles might be challenging due to this high kinetic energy. The stacking and subsequent film coating of pellets are the primary advantages of this manufacturing method.

Processing parameters¹⁸

1. Drying parameters

Temperature

The rate of drying increases as the incoming air temperature rises.

Humidity

A key factor in the compounds drying process is humidity. When compared to intake air with high humidity, the Low humidity in the input air speeds up the drying process.

B) Granulation parameters

Placement of nozzle

To improve drying, the nozzle location should be changed according to the bed height.

Spray rate

Optimizing the rate of spray will help avoid over granulation.

Spray pressure

Continuous pressure monitoring is necessary because variations in pressure can result in incorrect granulation and drying processes.

C) Coating parameters

Distance of spray nozzle

The distance between the spray nozzles is significant in determining the coating process because the greater the distance, the more the coating solution evaporates, and the smaller the gap, the more the particles or dosage forms are moist.

Droplet size

The efficiency of coating is negatively correlated with droplet size. The homogeneity of the solution's coating increases with decreasing droplet size.

Spray rate

Neither too fast nor too sluggish of a spray rate is ideal. Maintaining the ideal spray rate is necessary for optimum coating.

 Spray pressure

Spray pressure affects the coating solution's atomization.

Pelletizing

Various pelletizing techniques are available using fluid bed technology, on the substrate's       characteristics and the products' intended use²¹.

Direct Pelletizing

The practice of making pellets straight from powder is known as "direct pelletizing." The forces of acceleration involved in the process which leads agglomerates are formed. These agglomerates are subsequently dried after rounding out into uniform, dense pellets. Spray granulation is an additional option to direct pelletizing. With the right formulation, Pellets can be compacted to create tablets or automatically dosed and placed into capsules. The smooth surface and even shape make it perfect for applying a precise film for a controlled release.

 Pelletizing by Layering

The initial material can be either a pellet or a starting grain. Layer by layer, the layering substance is sprayed on to build up the pellet to the necessary size and active ingredient content. Appropriate layering materials include powder, binders, suspensions, or solutions. In order to combine a variety of diverse functions into a single pellet, active ingredients can be applied layer by layer onto a carrier in the form of powder or solution. Pellet accumulation layer by layer; produces layered spherical pellets with a dense, uniform surface, little hygroscopicity, optimal dosability, and a restricted grain size distribution around a starting core¹⁰.

Pelletizing by Spheronizing

The oldest known industrial pelletizing method is this processing choice. After blending all the ingredients, liquid is added to create a wet dough, which is then run through an extruder with predetermined dye sizes. A high yield of uniformly sized pellets is guaranteed. During start of spheronization, the extrudates fragment into tiny pieces. However, there is a 500µ minimum particle size limit. This process is a bit laborious even though it has a high degree of reproducibility because it includes a lot of steps, such as dry blending, drying, spheronization, extrusion and wet massing, and With a large total product contacting surface, it makes use of a range of equipment. The aforementioned procedure produced spherical pellets from extruded products or granulates. It goes without saying that because of the intense rolling motion used in their production, the pellets' surface will be smooth. A subsequent functional coating that is equally uniform is made possible by the uniform particle size. In many pharmaceutical applications, a formulation containing 20–50% microcrystalline cellulose is often the only way to achieve a uniform particle size¹⁰.

Coating (pelletizing) / powdered layering

By applying a powdered or liquid substrate (such as a solution, suspension) to inert carriers like sugar spheres, the latter creates pellets or spherical forms of the substrate. After that, the pellets are coated for controlled or modified release dose formulations. Three types of common coating materials can be distinguished: water-soluble and insoluble polymers, and waxes. Polymers are insoluble in water can be used. Aqueous systems like latex or pseudo latex dispersions or organic solvent systems. Aqueous dispersions have become more popular due to environmental concerns about the use of organic solvents.

APPROACHES

Advantages of fluidized bed processor

• A quick mixing process, constant temperatures, and concentrations.
• Acceptable for both big and small activities.
• Smaller surfaces are needed because of the high rates of heat and mass transmission.
• Air drying and the solid material are in opposition to one another¹¹.

Disadvantages of fluidized bed processor

• Fine particle beds that bubble up are less effective and more unpredictable.
• Breaking apart of particles is widespread.
• Particle collisions cause the walls of vessels and pipes to deteriorate.
• Irregular flow patterns (difficult to predict).
• Fine particle beds that bubble up are more unpredictable and less effective¹⁸.

Application of fluidized bed processor

• Fluid bed Drying - Fluid bed drying is an excellent method for drying solids. During the fluidization process, the entire surface of each particle is drained of liquid. Two advantages are the ideal drying time and outstanding heat exchange.
• Fluid bed Granulation/ Agglomeration - A contemporary technique for making granulates from powder using liquid bridges is agglomeration in the fluid bed. The liquid that is sprayed may be water, an organic solvent. The wet powders are either dried or chilled.

• Powder coating - Selective manipulation of product properties is made possible by the use of protective films in contemporary film coating. Applying the coating material with extreme consistency is essential during coating. The coating needs to provide a full seal that is impervious to tearing or mechanical harm. Film coating is an extremely versatile process that is technically demanding.

• Pelletizing - Pelletizing is the process of combining and hydrating powder. Additionally, a solvent or binding agent may be added simultaneously. Agglomerates are spheronized into homogeneous, dense pellets by the centrifugal force. Direct pelletizing or stacking can be used to achieve specific product qualities¹⁸.

Critical material attributes effects on the pelleting process crucial quality attributes¹⁵

Table No.1.Critical material attributes effects on the pelleting process crucial quality attributes15

 Innovative technologies²¹

Although the capsule is the most popular drug application form, the clearly described multi particulate pellet units can be used to formed into a number of different forms. Tablets can be created by further compressing the pellets, which are then released as multiparticulates once the tablet dissolves in the stomach. Oral suspensions made of pellets less than 500 µm in size can be utilized without leaving the mouth feeling sandy. It takes specific technologies that produce micropellets to reach such small pellet sizes. Such pellet particle sizes are practically possible with conventional coated and fluid bed drug stacking technologies such as the Rotor, Wurster process is limited to drug stacking techniques. Along with the aforementioned well-established and current pelletizing technologies, some cutting-edge and novel technologies have recently been investigated, opening up new possibilities for product qualities and formulations. 100–500 um is a tiny pellet size range, a surface of smooth particles, a high density, high drug loading, and a uniform particle size distribution ²².

CPS™ Technology (Controlled Release Pelletizing Technique)

CPSTM Technology produces matrix-type pellets through a direct pelletization process. Both the pellet formulation and the pelletizing procedure affect the release properties of API from CPSTM pellets. Advanced fluid bed rotor technology, known as CPSTM, enables the batch preparation of matrix pellets with specific properties. It is possible to develop extremely low-dose, highly effective medications as well as high-dosed APIs for CPSTM matrix pellets, with drug concentrations ranging from less than 1%-90% or more. Because the CPSTM Technology differs from the well-known Rotor system, it uses a conical rotating disc along with other components to guarantee directed particle movement.

The CPSTM formulations can also include other excipients and the like, even though the most common application for microcrystalline cellulose powder is as a basic excipient. The CPSTM Technology does not require inert starting beads. The pelletizing liquid is used to wet the starting powder (blend) until a certain moisture level is reached, at which point spherical pellets start to form. Dry powder can be added to the process as an alternative. Lastly, the pellets are dried using either a traditional fluid bed dryer setup or the CPSTM.

MicroPx™ Technology

The MicroPxTM Technique produces matrix-type pellets through a fluid bed agglomeration process. Particles may have a high drug loading of usually 95% and a relatively small size, such as less than 400 µm. The pellet matrix can incorporate pharmaceutical excipients have functional properties, like those for controlled drug release or enhanced bioavailability. In this technology operates on a continuous fluid bed process; once more, starting cores are not needed for pelletization. The MicroPxTM technology's design offers an optimal product flow in a rectangular processing chamber at both the pilot and commercial scales. In order to establish a directed air stream that enables a directed product transport over the plate towards the classifying unit, the fluidizing air is directed into the processing area using an input air distribution plate. The air distribution plate has one or more    spray guns installed. A set of cartridge filters will control the amount of dust that is blown back into the processing area. An online classification unit called a zigzag sifter is installed at the front of the processing chamber to keep product that is too small in size during the process and to continually discharge well-sized product from the current process. The particle size of "good" product that needs to be released from the process is determined by modifying the classification air flow.

Comparison of CPS™ Technology and MicroPx™ Technique

When drug-loading particles exceed 90% need to supplied in a size range of particle 100–400µm, MicroPxTM technology is the most practical option. These tiny pellets are commonly required for taste-masking applications as well as for compressing pellets into tablets. Similar particle size ranges can be provided by CPSTM; normally, API loads are lower targeted and achieved; a typical load range is between 1 and 75%. Because the CPSTM processing parameters, specifically the shape and speed of the rotating disc, can be adjusted to effectively control the densification. The best use case for CPSTM matrix pellets is a modified drug release from the matrix. The CPSTM matrix pellets can also be coated with any functional coating to produce a specific in vitro dissolution profile.

Technology of ProCell TM

ProCell ^TM Technology is a spouted-bed type of pelletizing process that creates very concentrated pellet-shaped particles. Ideally, no extra excipients are needed to form ProCell ^TM particles, which in this case result in particles made entirely of pure API. In the ProCell ^TM spouted bed, particles are fluidized by vertical process airflow, which instead of using the usual bottom screen or input air distribution plate used in conventional FBD processing, permits process air to enter the processing chamber through side slots. The fluidizing velocity of the process air drops off dramatically as the processing chambers cross section widens considerably toward the top. The processing chamber's particle circulation and flow pattern are regulated by this effect. Spray nozzles are usually found near the bottom. Like the CPSTM and MicroPx ^TM technologies, the ProCell ^TM Technology uses a direct granulation and pelletizing process. It is possible to process solutions, suspensions, emulsions, or similar substances that contain the API without the need for inert starting beads. When a material is melted and processed, ProCell TM Technology works best because it eliminates the requirement to evaporate organic solvents or water and uses spray solidification and agglomeration to form granules and pellets. High throughputs and economical procedures are made possible in this way. A sieving  unit or a zigzag sieve can be used offline or online to fractionate the continuously arising product quantities. In any case, product losses can be minimized by recycling the separated material back into the process²⁴

Marketed Formulation of pellets^25-30

Table No.2. Marketed Formulation of pellets