Yang Fluidization, Solids Handling, and Processing

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In the pharmaceutical industry, when a functional coat is applied to a particle containing an active ingredient (drug), it is common to monitor the release of the active ingredient using in vitro dissolution. The rate at which the drug is released under a set of well-controlled conditions gives valuable information on the expected release of the drug within the body. This method is much easier to perform and less costly than in vivo testing using human or animal subjects. Thus, so long as a correlation between the results from in vitro and in vivo testing exists, the preferred test method for quality control is via a dissolution test. However, the fact that particles with the same amount of active ingredient and seemingly similar coats can give quite different release characteristics suggests that the morphology of the coat is an important factor in predicting the performance of a coated particle. There is an abundance of literature outlining case studies using combinations of various additives and coatings to tailor the release of an active ingredient (Mehta and Jones, 1985; Rekhi et al., 1989; Jozwiakowski et al., 1990; Wan and Lai, 1991; McGinity, 1989; and Gilligan and Po, 1991). Several studies (Weiss and Meisen, 1983; Mehta and Jones, 1985; Rekhi et al., 1989) have taken electron micrographs of cross-sections and the surface of coated particles, and qualitative differences in the morphology of the coat were discussed. However, to date there appears to be no work done in quantifying the morphology of the coat in terms of the operating parameters of the equipment used in the coating process. Some of the factors to consider regarding product quality when scaling up a process are discussed in Sec. 2.5.

2.5Design Criteria

For a given coating application, the choice of what equipment and processing conditions to use must be based on prior experimental experience. There is no way, at present, to choose all the variablesa priori. Experimental verification for the specific application under the specific conditions, using the desired coating formulation, must be performed for all new processes. However, there are many guidelines available to aid the engineer in making rational choices and, thus, reducing the scope of the variables to be searched. The following section attempts to catalog some of the more important design concepts to aid in the selection of equipment and conditions.

Fluidized Bed Coating Equipment. In reviewing the literature, it is evident that there are a great many variations in fluidized bed equipment used in coating applications (Olsen, 1989a and 1989b; Jones, 1985; and Mehta,

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1988). Nevertheless, we may categorize all the equipment into four main groups. Each group is discussed below

Conventional Spouted Bed. The use of a conventional spouted bed (see Fig. 2a) is favored in the application of coatings to agricultural, food, and larger pharmaceutical products. A restriction in using this type of equipment is that the material to be coated must bespoutable. Spoutable means that the particles should be Geldart type D solids, implying that they have diameters typically 2 mm and greater (see Geldart, 1973 for a more complete definition). Gas velocities must exceed the minimum spouting velocity, and the height of the bed must not exceed the maximum spoutable height. Another important feature of the spouted bed is the angle of the air (gas) inlet cone. Correlations for these quantities are given by Liu and Litster (1991), Mathur and Epstein (1974) and Kucharski and Kmiec (1983). Since the particles are large, their velocity when leaving the top of the spout is quite high, and attrition may be excessive for friable particles or coatings. The location of the nozzle can either be at the base of the spout or in the fountain region above the bed as shown in Fig. 2a. Due to size dependent circulation rates through the spray zone (Robinson and Waldie, 1978), uniformity of coating thickness may be a problem, especially for a wide size distribution of feed material.

Fluid-Bed with Draft Tube. The use of fluidized beds with draft tube (see Fig. 2b) is the preferred method for the application of functional coatings to particles in the pharmaceutical industry. The term functional refers to the fact that the coating provides a delay in delivering the active ingredient contained in the fluidized solids, e.g., sustained release and enteric coatings. The application of the draft tube to particle coating is attributed to Wurster (1957 and 1966), and the draft tube is often referred to as a “Wurster Insert.” The purpose of the draft tube is to channel air (or the fluidizing gas) up through the center of the bed, thus, entraining particles with it. The circulation of solids obtained with a draft tube is well controlled, repeatable, and quite stable. This property of these beds allows the production of a batch of coated material with a relatively narrow distribution of coating thickness.

The use of a draft tube overcomes the difficulty of spouting only large particles. In fact, particles in Geldart’s A, B, and D particle categories have all been successfully coated using these devices. For smaller particles (300 µm and smaller), it has been found (Jones, 1985) that the length and angle of the expansion chamber above the bed are crucial in reducing carryover and in maximizing the circulation rate of the particles through the

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spray zone. The location of the spray nozzle is almost always at the base of the draft tube (bottom spraying), and dual fluid nozzles are used most often.

Conventional Fluid-Bed Granulator. In a conventional fluid-bed granulator, Fig. 9a, the fluidizing gas is again preferentially fed to the center of the bed. This causes particles to be dragged up in the center with the upward moving gas. The net result is that the particles circulate within the bed but in a less ordered or more chaotic manner than in conventional spouted beds with/without draft tubes. The formation of a spout is not required, therefore allowing a wide variety of particle sizes to be used. The coating liquid is nearly always sprayed downwards from the top of the bed which has the advantage that the nozzle may be removed during operation if it becomes clogged. Due to the less ordered circulation of particles, this equipment is rarely used for sustained or enteric coatings, although application of moisture barriers and cosmetic coats are common. This equipment has also been used successfully to apply hot melt (solventless) coatings.

Rotor Granulator. The last type of equipment used for powder coating is the rotor granulator, Fig. 9b. This equipment utilizes a variable speed rotating disc at the base of the bed. Fluidizing air (gas) flows between the edge of the disc and the bed wall upwards through the bed of solids. The combined action of the fluidizing gas and rotating disc causes the bed solids to circulate in the direction shown in Fig. 9b. Since the carryover of solids is small, the expansion space above the bed is small. Thus, a large volume of solids can be processed in a relatively small piece of equipment. The rotor granulator can be used in standard coating applications but its main advantage is its ability to apply a layer of powder to a solid substrate. Dry powder can be fed simultaneously with a liquid binder solution. With the correct location of feeds, the solids are first wetted by the liquid and then covered with a layer of powder. Successive cycles of wetting and powder layering allow the rapid buildup of powder on the substrate solids. This technique is particularly useful when the solute (coating powder) cannot be dissolved or slurried and when large amounts of active ingredients must be applied to a substrate solid.

Air (Gas) Handling Equipment. Both the quantity and the quality of fluidizing gas are important considerations in the design of a coating system. In general, the more fluidizing air (gas) that can be used, the greater the spraying rate and the shorter the processing time for a batch. However, other considerations, such as excessive attrition and coating mass uniformity, may well determine the maximum air flow rate and batch processing time. A

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typical air handling system for a pharmaceutical coating process (Olsen, 1989a,b), is shown in Fig. 10. For processes in which the cleanliness of the final product is not so important, the air handling may be simplified. Nevertheless, most systems will contain one or more of the following: humidity control, filtering, and heating.

Figure 10. Elements of a typical air handling system for fluid bed coating.

Humidity Control. Humidity control is important for both aqueous and organic based solvent processes. For sprays containing aqueous solutions, the inlet air humidity directly affects the mass of water which can be absorbed by the gas. Clearly, the drier (lower dew point) the inlet air is, the greater the amount of water that is needed to saturate it and, hence, the greater the spraying rate can be. Studies by Liu and Litster (1993b) on a conventional spouted bed showed that the maximum spray rate, defined as the maximum spray rate for which the spout did not collapse, lies below the theoretical limit corresponding to saturated air leaving the bed. It was found that the limit of saturation is approached as the spouting air velocity is increased. For spouted beds with draft tubes, it is common to assume that the maximum limit for spraying corresponds to the exit air being saturated, although this rarely happens.

For organic solvent processes, the humidity of the air can also play a role in the product quality. One particular problem which can arise is that of condensation of water in the bed. In the vicinity of the nozzle, local cooling may be experienced due to solvent evaporation (Smith and Nienow, 1982), as discussed in Sec. 2.3. As a consequence of this local cooling, the temperature

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may fall below the dew point of the air, and local condensation of water may occur with the result of product and coat damage. Clearly, this effect can be controlled by adjusting the humidity of the incoming air. If wide swings in humidity are expected, it may be necessary to dehumidify the air some of the time while humidifying it at other times.

Filtering. Contamination of product by foreign particulates in the fluidizing air can be minimized by the use of filtration. A trade-off may be required between air purity and increased compression costs due to higher filter pressure drops. For coating at close to ambient conditions, the cost of air handling is usually only a small percentage of the total cost, and low particulate loadings in the inlet air are easily achieved.

In addition to inlet gas filtering, it is usually necessary to use some form of filter downstream of the fluidized bed to avoid solid carryover. For fairly large particles, this is usually achieved by bag filters or screens; for very fine powders, a baghouse and cyclones may be necessary.

Heating. Along with controlling the humidity of the air, the other option for increasing the spraying rate of liquid, and hence reducing the processing time per batch, is to add heat to the system. The most common method for doing this is to heat the fluidizing air prior to feeding it to the bed. Care must be taken not to use excessively high inlet air temperatures when the active ingredients or coating material are heat sensitive; again, this is important for pharmaceutical, food, and agricultural products.

Recently, the use of microwave heating has also been applied successfully to coating processes. The use of internal heating surfaces is usually not practical since these would tend to clog and foul during the process.

Control of Fluidizing gas. For typical coating operations, a highvolume, low-head centrifugal blower is most commonly used. The location of the blower is most often at the exit of the system, thus causing the system to operate under a slight vacuum. This offers several advantages. First, fine particulate emissions to the surrounding area, through leaking seals etc., are eliminated; likewise, solvent emissions are also eliminated. In addition, the possibility of tripping explosion relief devices, through over-pressurizing the bed, are eliminated.

Distributor Plate Design vs. Split Plenum Designs. The fluidized bed with draft tube and conventional granulator designs, given earlier in this section, require the major portion of the fluidizing gas to flow through the center of the bed. There are essentially two ways to do this, as illustrated in Fig. 11. In Fig. 11a, a typical gas distributor plate for a single plenum design

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Scale Up of Process. The scale up of fluidized bed coating processes has received little attention in the literature. Current practices in the pharmaceutical industry are reviewed by Mehta (1988). The basic approach described by Mehta (1988) is to scale the air flow and liquid spray rates based on the cross-sectional area for gas flow. This seems reasonable except for the fact that in the scaling of the equipment, the height of the bed increases with increasing batch size. For this reason, a time scale factor is also required.

Some typical fluid bed capacities used in the pharmaceutical industry are given in Table 2. From this information, it can be seen that for beds up to 450 mm (18") in diameter, one draft tube is typically used. The diameter of the draft tube is nominally one-half the bed diameter. For larger beds, the use of multiple draft tubes, 225 mm in diameter, is common. Also shown in Table 2 are the heights of the draft tubes used in each bed. Since the solids in the bed are filled close to the top of the draft tube, the capacity of the equipment is determined by the diameter of the bed, the height of the draft tube, and the density of the bed solids. An example illustrating the scale-up procedure is given below:

Test runs using a 150 mm diameter fluid bed coater indicated that a batch of 2 kg of material could be coated using a liquid spray rate of 10 ml/min for 50 minutes and a fluidizing gas rate of 40 scfm. It is desired to scale-up this process to a batch size of 200 kg of bed material. For the scaled up process, determine: the bed size; the liquid and air flow rates; and the new run time.

From Table 2: choose a 800 mm diameter bed with 3–225 mm diameter draft tubes. The air flow and liquid spray rates are scaled on draft tube diameter:

New air flow required = 40[3π(225)2/4)/(π(75)2/4) = 40(27) =1080 scfm

New coating spray rate = 10(27) = 270 ml/min

The processing time is calculated based on the same coating mass per particle, thus:

New coating run time = t

Coating per particle = (270)(t)/(200) = (10)(50)/(2) ml/kg

Therefore, t = (200)(50)(10)/(270)/(2) = 185 min (3.1 h)

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Table 2. Typical Capacities of Fluidized Bed Coaters with Draft Tubes used in the Pharmaceutical Industry (Mehta, 1988)

* Typical air flowrates are on the order of 3–5 m3/s/(m2 of draft tube)

From the scale-up example given above, it is clear that the material and energy balances for the two processes have been correctly scaled. However, this scaling neither addresses nor guarantees similar product quality between the processes. From Sec. 2.4, we recall that the product quality is a strong function of the number of passes a particle makes through the spray zone and the variation in the amount of coating that a particle receives each time it passes through the spray. Both these quantities are affected greatly by the scaling process. Unfortunately, there appears to be little work published in the area of quantifying the coating mass uniformity and morphology in large equipment. Qualitative arguments are given below to describe some of the interactions which should be considered when scaling a process.

(i)Longer processing times. With all other variables fixed and for particles and coatings which do not suffer appreciable attrition, the effect of longer processing times is to improve the coating uniformity. The reason for this is that as the run time increases, so does the number of particle passes through the spray. In general, it is better to add a smaller amount of coating to a particle and repeat the process many times than to do the opposite.

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However, in most practical situations, both the particles and the applied coating material abrade as particles slide past each other, and a compromise between long processing times and excessive attrition must be made.

(ii)Larger Diameter Equipment. With all other variables unchanged, the effect of larger diameter equipment, which infers larger diameter draft tubes, is to worsen the coating uniformity. The reason for this is that as the diameter of the draft tube increases, and assuming the voidage in the draft tube does not change, then the sheltering of particles close to the center of the draft tube is more pronounced, causing Var(x) to increase. This concept is discussed in more detail elsewhere (Cheng and Turton, 1994).

(iii)Longer Draft Tube. Even with all other variables unchanged the effect of a longer draft tube on the coating uniformity is unclear. Two opposing effects come into play when the draft tube length increases. First, as the bed height increases, the mass flow of solids into the draft tube will increase due to the increased static head in the annulus. This generally increases the particle sheltering effect (since the voidage in the draft tube falls) and increases Var(x). On the other hand, the circulation time of the particles decreases, and the particles make more passes in a given time. This tends to improve the coating uniformity

Clearly, what happens when we scale up a process includes all of the above effects. Depending on the level of the scale up, it is conceivable that, in some cases, product quality might improve while, in other cases, it might worsen. In conjunction with the scale up, it may also be possible to change some of the equipment variables to compensate. For example, the circulation rate of solids is controlled by the gap between the bottom of the draft tube and the distributor plate. By adjusting this gap, it may be possible to counterbalance the effect of changing particle circulation due to scaling the process. Similarly, the use of multi-headed orifices, typically used in the larger draft tubes, may also counter the sheltering effect.