How To Optimize The Fluidized Bed Process (Chapter 8)

Key Points Of This Chapter

Multi-unit pellet systems (MUPS) have multiple therapeutic and technical advantages compared with single-dose large doses. They are evenly distributed in the gastrointestinal tract and have fewer adverse reactions; they can also reduce the risk of dose dumping and have stackable bioavailability.

The use of fluidized bed to prepare pellets is completely different from the extrusion spheronization method. This process is a coating and drug application process derived from the fluidized bed side spray process. Commonly used modules include: Wurster module, turntable cyclone module, in In addition to the pellet characteristics mentioned in this chapter, in the pellet coating and drug application process, there is actually another key indicator which is the hardness of the pellets. Currently, due to the lack of specialized characterization tools, a modified friability method is used. Characterization results in a lack of good discrimination in the data. In other words, the pellets lack a unified standard for evaluation, which makes it impossible to meet the process reproducibility.

Chapter 8 Pilling And Coating

01 Introduction

Controlled release formulations may be administered orally in single or multiple unit dosage forms. Among multi-component dosage forms, the most commonly used dosage form is pellets. It is an ideal dosage form that rapidly disperses or disintegrates in the stomach after oral administration, releasing drug particles. Pellets are agglomerates of fine powders or granules of raw materials and excipients. They consist of small, free-flowing, spherical or hemispherical solid units, typically from about 0.5 to 1.5 millimeters, and are commonly used for oral administration. Polymer-coated multi-pellets or multi-unit pellet systems (MUPS) offer several therapeutic and technical advantages over single-dose bolus dosage forms. Pellets or multiple pellets are small in size (<2mm), evenly distributed in the gastrointestinal tract, and have few adverse reactions. Pellets also reduce the risk of dose dumping and have stackable bioavailability compared to single-dose bolus doses. Pellets can be filled into capsules or compressed into tablets for administration. Pellets provide great flexibility in the design and development of solid dosage forms. They are free-flowing and easy to fill, resulting in uniform and reproducible fill weights for capsules and tablets. Processing technology plays a vital role in the development of pellets. For example: physical force first binds the primary particles together, and then the pellets are formed. The basis for the formation of pellets in any processing equipment basically follows the growth mechanism, which is determined by physical forces. There are many publications on the theory of pellet formation.

Several technologies are available for manufacturing pellets containing uniform drug distribution. The most widely used pelleting unit operation is the extrusion/spheronization method. Other technologies include high shear pelleting, melt pelleting, spray condensation, etc. The scope of this chapter will cover pelleting using fluidized bed processors and their different processing modules. Drug application is the deposition of drugs on the surface of the carrier. The drug application process involves the continuous deposition of physical layers of drug from solution, suspension or dry powder on the drug core, which can be crystals/pellets or inert spheres of the same substance. Use the rotary fluidization module to achieve powder-to-pellet production by loading solution/suspension or powder onto inert spheres (such as sucrose pellets or microcrystalline pellets). The most common way to coat pellets with drugs on the matrix is to use a Wurster module for coating.

When dosing a solution/suspension, the drug particles are dissolved or suspended in the binding fluid. By controlling the rate of application of the solution/suspension, agglomeration of the carrier pellet core can be minimized. In powder application, the binder solution is first sprayed onto an inert sphere and then the drug powder is added. Solution application in a fluidized bed processor can be accomplished by top spray, bottom spray, or by using a rotating processor unit in the fluidized bed. Because pellets are spherical and have a low surface-to-volume ratio, they are ideal for modified release applications. Drug-coated pellets composed of different drugs can be mixed and formulated into a dosage form. This approach facilitates the delivery of two or more drugs that are chemically compatible or incompatible at the same location or at different locations in the gastrointestinal tract. Even pellets with different release rates of the same drug can be provided in one dosage form.

02 Wurster Pellet Coating

The Wurster coating machine is a bottom-jet fluidized bed coating machine. In addition to functional coating of pellets, it is also used for coating solutions or suspensions. The Wurster module has three areas: the liquid spray area in the column, where the pellets are rolled into the guide tube by the negative pressure in the column and come into contact with the liquid; the rising atomization area, where the pellets rise with the atomized airflow, and the liquid is atomized and sprayed to The area on the pellets is called the rising spray area; the descending drying area, where the pellets fall back to the drying bed from the highest point, is the descending drying area. The nozzle provides a liquid solution and atomizing air, which breaks the solution into small droplets and forms a spray area in the cavity. As the pellets pass through this zone, they acquire the coating solution in the form of droplets. As they move through the fluidized bed, the droplets are dried by a stream of hot air, forming a layer on each pellet. As the pellets exit the guide tube and enter the expansion zone of the fluidized bed, their fluidization rate slows during the drying process. The dried pellets enter the bed area again for another solution or suspension application.

The air distribution plate directly under the Wurster column has a higher opening area than the air distribution plate outside the column, resulting in a higher central air velocity in each center column. The air flow in the lower bed area keeps the material in a boiling state and can be sucked horizontally into the gap at the bottom of the Wurster column. Therefore, the height of the Wurster column itself, the gap between the Wurster column and the air flow distributor, and the pressure through the atomization zone control the rate of carrier flow into the spray zone. During the coating process, the mass gradually increases, so the gap height of the column can be adjusted to keep the pellets entering the spray zone smoothly. The coating or lamination of different droplet layers around the pellets provides a uniform coating thickness. After several wetting-drying cycles, a continuous film is formed, the thickness and composition of which depend on the material used. The tendency of agglomeration between two particles or between several particles also occurs at this stage.

03 Rotating Fluidized Bed Pill Making

Centrifugal Pill Making

An alternative technology for producing pellets is single-pot methods, where they are produced, dried and coated in the same equipment. They are step-by-step processes carried out in one machine, for example using a high shear mixer or rotating fluidized bed processor. Using one machine for the entire process ensures batch-to-batch repeatability, reduces production time and costs, and automates the process. The rotating fluidized bed module of the fluidized bed was originally developed to perform the pelletizing process and was later expanded to perform other unit operations, including the preparation and coating of multi-unit pellet systems, and is now used to apply drugs via powders and solutions/ The drug is suspended and polymer coated for pill making. Jager and Bauer reported that rotating fluidized bed production of pellets was superior to traditional top spray pelletizing technology. In this device, the traditional air flow distributor is replaced by a rotating disk. The material to be pelletized is loaded onto the rotating disk, and the binder solution is tangentially sprayed into the cavity. The centrifugal force produces a spiral material movement. This type of movement is caused by three directional forces: the vertical upward force is It is provided by the gap or slit airflow around the rotating disk; the force for the material to flow to the center is provided by the gravity decomposition of the material on the inclined plane of the turntable, or it occurs naturally due to the lowest airflow speed in the center and the material falls back due to gravity; the force pushing away from the center is It is provided by the centrifugal force generated by the high-speed rotation of the rotating disk. Pellets produced in a rotating fluidized bed processor have lower porosity than conventional products in fluidized bed processors. In 1972, the patent for rotor technology was granted to coating equipment and coating materials, and subsequent patents were granted to the coating of spherical pellets. Different manufacturers of these units offer rotor modules of different designs, but the principles of motion in the units are similar.

The double-chamber structure is similar in principle and design to side-spray or rotating fluidized bed pelletizing. It has an independent double-chamber structure and operates as an independent unit by opening or closing the inner cavity. For example, when the inner cavity is closed, liquid spraying or powdering can be carried out independently until the MUPS reaches the required size, and then the inner cavity wall is raised. , the pellets enter the drying area, and the small pellets are lifted upward by the fluidizing air and return to the forming area across the inner wall. This cycle is repeated until the required residual moisture level in the pellets is reached.

Korakianiti et al. studied the preparation of pellets using a rotating fluidized bed. The authors concluded that rotational speed and liquid volume significantly affected the average diameter of the pellets, and they proposed an equation to show this correlation. Piśek et al. studied the influence of rotational speed and turntable surface on the production of pellets. They used a mixture of pentoxifylline and microcrystalline cellulose to produce pellets using Eudragit NE-30 as the coating material. The results show that the disc surface and rotational speed have an impact on the shape, surface and size of the pellets, and have less impact on the density, moisture content and yield of the pellets; they found that compared with the smooth surface, when the rotational speed increases, the micropellets The surface of the pellets is rougher, where increased rotational speed produces more spherical pellets with larger diameters. Kristensen and Hansen compared fluidized bed top spray pelletizing and rotary processor pelletizing and concluded that the rotary processor had better operability in terms of obtained pellet size and was affected by the starting material flow characteristics. The impact is smaller. Iyer et al. compared solutions containing phenylpropanolamine hydrochloride (PPA) and binders through top spraying and rotation. They concluded that the surface smoothness of pellets made through rotation technology was better. , better in terms of yield and uniformity of drug content.

Bed moisture content is a key characteristic. The three main factors that affect bed moisture content are air flow, air temperature and spray rate. Low moisture content in the bed will result in rough and porous pellets as they grow through breakage and dosing mechanisms. A reduction in air flow rate or interstitial air pressure will reduce the spiral flow pattern in the bed. An increase in interstitial air pressure will result in higher moisture loss. , which helps reduce particle size. Environmental and other processing variables that may have an impact on the process should be controlled. This also applies to preparations being processed. By controlling for these external variables, the residuals will be smaller, allowing for a more accurate analysis of variance. Adding more water or binder solution will produce larger pellets, but it may produce a larger particle size distribution (PSD).

Solution Or Suspension Pellet loading

Drug application is a slow growth mechanism, which mainly involves continuous polymer material fragments and fine powder on the already formed mother core. Coating microcrystalline or sucrose pellets is a process that allows the drug to be evenly distributed on the carrier excipient. This technology can be used for active agents or intermediates dispersed in liquids. During the drug loading step, the number of pellets remains constant, but as the pellet size increases with time, the total mass in the system increases. A rotating fluidized bed is used to load the active drug suspension or solution onto the sucrose pellets. Pellets are produced that are cored and subsequently coated with polymers to impart different release behavior. Baki et al. reported the importance of surface free energy in understanding the drug application process. The spreading coefficient plays an important role in the adhesion of layered drug solutions on substrates. The authors prepared carrier pellets from a mixture of hydrophilic (microcrystalline cellulose) and hydrophobic (magnesium stearate) components in different proportions. These pellet cores are coated with a drug-containing solution in a fluidized bed device, with or without the addition of hypromellose (HPMC) as a binder component. The composition of the pellet core was changed to evaluate the bonding between the pellet core and the coating layer and its mechanical properties. The authors pointed out that the retaliation efficiency and mechanical properties of hydrophobic pellet cores can be improved by applying adhesives. Exfoliation of the HPMC-containing layer was observed with hydrophobic pellet cores, but this phenomenon was not detected with hydrophilic pellet cores. Hileman et al. reported that by loading active drug suspension onto sucrose pellet cores, the pill cores were first prepared in a rotating fluidized bed, and these immediate-release pellets were treated with an aqueous ethanol solution of ethylcellulose/HPMC in the same device. Coating without additional processing and processing steps. Mise et al. studied the effects of API particle size and wettability on high drug loading (>97) formulations. Acetaminophen (APAP), ibuprofen (IBU), and etozamide (ETZ) were used as model drugs based on their differences in wettability and particle size distribution. Regardless of the drug used, pellets with an average particle size of 100-200 μm and a narrow PSD can be prepared. The sphericity of IBU and ETZ pellets is higher than that of APAP pellets, while the pellet strength of APAP and ETZ pellets is higher than that of IBU. The relationship between drugs and pellet properties shows that the wettability and particle size distribution of the drug are key parameters affecting sphericity and pellet strength, respectively. In addition, the dissolution profiles of pellets prepared from drugs with poor water solubility (IBU and ETZ) showed rapid dissolution (20min>80%), which was due to improved wettability.

Powder Layering Pill Making

In 1992, Jones et al. obtained a patent for this process. This process claims to have the advantage of coating the drug substance with a relatively small amount of liquid, making this coating process more efficient. The most commonly used binders in powder lamination are gelatin, povidone, carboxymethylcellulose and hypromellose. A typical process involves a rotating fluidized bed with tangential nozzles. Sugar pellets or MCC pellets are loaded into the rotor, and powdered API is fed into the machine through a precision powder feeder. A binder solution coats the active powder to the sugar pellets. The carrier size of the starting MCC pills or sugar pills will depend on the final drug loading. Higher drug loading requires smaller starting carrier pellets, but this extremely small particle size carrier may cause self-agglomeration. And it is caused by adhesion due to the combined use of medicine. Therefore, injection rate, slot air and inlet air temperature are the main factors that must be monitored. The most critical factors are the binder spray rate, powder feed rate and air inlet flow rate. Drug powder that is not completely adhered to the carrier will be carried away by the air flow, affecting product output and quality. The particle size and flow characteristics of powdered API must be suitable for powder coating. It is usually recommended to use micronized API, and a high-precision screw feeder is required to complete API powder feeding. In order to obtain better results, the powder particle size should be <30 μm.

Several advantages are mentioned in the powder application literature:

(1) A lot of time can be saved by adding the API in powder form rather than dissolving or suspending it in a liquid and coating it on the pellet core.

(2) Compared with solution/suspension drug loading, high drug loading capacity can be achieved.

(3) Multi-layered pellets with multiple active drugs in the same pill core can be completed by loading different drugs in sequence and coating the isolation layer.

(4) Reduce or eliminate the use of organic solvents.

(5) Use inert pellet cores as the starting substrate of the drug or directly coat the API crystals.

(6) Due to the centrifugal force in the rotor, sphericity is obtained on the pellets at the end of the process.

Some of the disadvantages mentioned in the literature are:

(1) The drug loading capacity is limited by the size of the pill core carrier.

(2) The adhesive spray rate and powder feeding rate need to be closely monitored throughout the entire process. How to synchronize perfectly has always been a problem.

(3) If the API has poor fluidity, additional excipients may need to be added to increase fluidity, thereby greatly reducing the drug loading capacity.

(4) Since 100% adhesion cannot be achieved, there is always fine powder taken away by the airflow, resulting in a yield loss of between 10% and 20%.

(5) The powder needs to be transported as close as possible to the wet pellets to reduce powder loss. However, in actual operation, the equipment structure cannot accurately deliver powder to the wet pellets.

04 Pellet Characterization

Regardless of the preparation process used, pellets may be evaluated as follows:

(1) The moisture content in the pellets should be evaluated after drying.

(2) They should be nearly spherical and have a smooth surface, both of which are considered optimal properties for subsequent film coating. These pellets are mainly designed to meet appearance, taste masking, stability, enteric release or controlled release purposes. The coating thickness of the pellets must be uniform to achieve the properties of the final product. For uniform coating thickness, formulation, equipment and process variables are typically selected based on reproducibility of parameters such as particle size distribution, surface area, shape, surface roughness, friability, etc.

(3) The particle size range should be as narrow as possible. The optimal size of pellets for pharmaceutical use is considered to be between 600-1000 μm. Uniform particle size distribution and friability are two physical properties that pellets must possess. Usually, pellets are also polymer-coated. For film coating, in addition to spherical shape and smooth surface, a narrow size distribution of the pellets is a prerequisite. Particle size distribution affects coating performance and drug release rate. Pellets should possess high hardness, low porosity, non-friability, and high density so that they can be processed during coating, screening, and encapsulation steps without losing the drug from the surface.

(4) According to Vertommen’s report, the shape of pellets can be evaluated by three factors: ringness, roundness and sphericity. The purpose of these parameters is to evaluate the aspect ratio of pellets. For perfect spherical pellets, the length The diameter ratio is 1.

(5) Pellets should contain as much drug content as possible to keep the size of the final dosage form within a reasonable range.

05 Summary

Pellets are multiparticulate dosage forms that can be prepared using different fluidized bed modules. Pellets can be prepared using a mixture of API and excipients with the addition of a binder solution in rotating fluidized bed processing modules manufactured by various equipment suppliers. The wet pelleting process employed is similar in most processing modules from different suppliers. The advantage of the spin processor is that it provides a module for the preparation, drying and coating of pellets as well as solution/suspension or powder dosing of API. The Wurster module is used for dosing solutions/suspensions of API and/or coated pellets and is the most widely used technology in commercial production in the industry. An understanding of formulation and process variables is critical to successful results. Pellets formed by any of these techniques should have narrow particle sizes, high hardness and sizes that can be further used in encapsulation or compression unit operations.