In the pharmaceutical and nutraceutical industries, fluid bed granulation is a widely used method of manufacturing flowable particles ideal for tablet compression.
In R&D, fluid bed granulation requires a fair amount of time to develop a robust process that yields acceptable product. In scaling up to commercial manufacturing, the same quality and results are expected with minimal development at production scale. This is not always the case if the critical parameters are not well defined on R&D scale. Following are commonly used, theoretical scale-up practices for fluid bed granulation. Most of these practices involve calculations that deal with simple concepts in geometry, psychrometry and thermodynamics. The calculations described will give reasonable target values for scaled-up parameters to reduce the number of scale-up trials that need to be executed. There will still need to be some optimization, since differences in machine geometry, product loading and other unforeseen issues will exist. These concepts and tools for optimization will be described in the following sections.
Basic Scale-Up Concepts
During scale-up, there are process characteristics and factors that need to be held constant to ensure similar product qualities. They are:
Fluidizing Velocity – The velocity of air flowing at the air distribution plate needs to remain constant in order to ensure the product is fluidizing in a similar way at different scales. The air velocity has to be selected such that it is higher than the minimum fluidization velocity of the largest particle, and below the transport velocity of the smallest particle (see Figure 1).
Just keeping the fluidization velocity within this range is not the only consideration. Depending on the velocity chosen within the range, the type of fluidization achieved will be different as illustrated in the diagrams shown in Figure 2.
The material characteristics, such as particle size distribution, density and batch size, are dynamic and will change during both granulation and drying processes (see Figure 3). Therefore, the type of fluidization achieved can change if the fluidization velocity is held constant throughout the process. Thus, many times it is necessary to adjust the fluidization velocity (by changing air volume) to maintain the type of fluidization required.
Liquid Evaporation Rate – During development, a balance between air flow and liquid spray is achieved that creates an evaporation rate that imparts moisture to the bed to create robust granules. In either case, during scale-up this balance needs to be maintained. So, if it is possible to hold inlet air temperature and dew point constant, scale up of spray rate becomes proportional to the increase in air volume.
Droplet Size – There are several empirically derived equations that model average droplet size created by a binary fluid nozzle, like those typically seen in fluid bed systems. The one common factor seen in all of these equations, given that the liquid properties do not change, is that the droplet size is mainly governed by the ratio of the mass-flow rate of the liquid to the mass flow rate of the atomizing air. Atomizing air pressure is not usually considered in these equations. Therefore, to keep droplet sizes similar, without measuring them or deriving a model equation for a specific nozzle design, the ratio of the liquid flow rate to the atomizing flow rate needs to be kept constant in scale up.
Since drying and top spray granulation almost always occur in the same unit, the scale up will be discussed as one topic. Using the concepts discussed above, critical process parameters will be calculated to keep the air velocity, the liquid evaporation rate and the droplet size constant at the larger scale.
Batch Size: In general, the optimal batch size is between 30% and 80% of the total volume of the granulator bowl. The maximum of 80% is used when the unit is a “bowl-in, bowl-out” designed machine. The 80% ensures that material will not be spilled when the machine is decompressed and the bowl is removed. Therefore, if the unit is equipped with bottom or side discharge, the batch size can be increased to 100% of the bowl volume, since the bowl remains in place during discharge.
To determine batch size weight, the bulk density of the product should be known. Since granulation processes typically reduce bulk density, the final bulk density of the product should be utilized in determining batch size. To maintain the same fill level, and assuming that the final product bulk density remains constant, the batch size increase can be calculated as follows:
X2 = X1V2/V1
X2 = Batch size of unit 2 (kg)
V2 = Bowl volume of unit 2 (L)
X1 = Batch size of unit 1 (kg)
V1 = Bowl volume of unit 1 (L)
If the new batch size will use a different fill level to, perhaps, maximize production quantities, it can be calculated as follows:
X = Batch size (kg)
V = Overall bowl volume (L)
p = Bulk density of product (g/cc)