How To Optimize The Fluidized Bed Process (Chapter 11-Part 1)

Key Points Of This Chapter

Statistical design of experiments is helpful for process scale-up, but for fluidized beds it is not possible to simply rely on process variables for scale-up, but rather to identify and account for all key sources of variability, to manage the variability through the process, and to predict Product quality attributes in design space.

Factors that need to be considered for amplification include: hydrodynamic similarity, fluidization velocity, bed moisture content and evaporation, bed height, bed weight (volume), cross-sectional area, droplet size, key operating variables and response, etc. .

Chapter 11 Process Amplification (Part 1)

01 Introduction

Currently, the industry’s interest in continuous processing lies in smaller volumes and floor space. For professionals, development and scale-up of production are the main challenges. Scale-up in the pharmaceutical industry is unique because it also requires laboratories and Explore on a pilot scale to produce products with specifications required for clinical trials at different stages. Appropriate quality management principles can help prioritize drug development studies to capture relevant influences on process performance. In a fluidized bed process, granule size is directly related to the humidity of the bed during granulation; therefore, controlling humidity during scale-up is critical.

Statistical experimental designs (eg, factorial and corrected factor designs) can generate mathematical relationships between independent variables (eg, process factors) and dependent variables (eg, product attributes). However, fluidized beds are a complex process that cannot be scaled up simply by relying on process variables. Identifying and accounting for all key sources of variability, managing variability through the process, and predicting product quality attributes in the design space all make The process is well understood. Scaling up from laboratory equipment to production scale units depends on equipment design. Material properties, such as granule size distribution, density and batch size, are dynamic and change during the granulation and drying processes.

Since airflow is one component of the drying capacity of a fluidized bed system, the air-to-material ratio per kilogram or per liter of product is critical to achieving linear scale-up. Another design feature is the cross-sectional area of the product container and how it is designed in the various sizes offered by the manufacturer. Using the relationship between process vessels of different sizes, the amplification of the adhesive spray rate can be calculated, and if the cross-sectional area is designed linearly, the spray rate amplification can be linear.

It is not feasible to perform a design of experiments (DoE) at every scale. Therefore, it is critical to understand the key physical transformations and consider the “key response variables” of device-independent scale-up/scale-down. The design space automatically grows if a wide range of process variables are used along with dimensionless or critical response variables. In terms of scale-independent parameters, design space can provide regulatory flexibility for technology translation, rather than re-establishing design space at each scale.

The added value of the application of Process Analytical Technology (PAT) during process development will add the necessary understanding of the interrelationship between process parameters and properties of the granules produced. Based on this knowledge, reasonable specifications can be selected for daily manufacturing and a process window or design space for unit operations can be implemented. Compared with traditional process control, online PAT measurement can monitor the entire manufacturing process in real time instead of collecting single point data at different time intervals. Therefore, process analysis techniques can be used to establish process trajectories for successful production batches.

Generally speaking, once the effects of process parameters have been thoroughly studied and optimized on laboratory-scale equipment, the next stage is to transfer the process to pilot scale and then to production scale. Most studies on amplification in the literature focus only on the amplification of fluidization processes. Relevant studies have proposed scale relationships to ensure that small-scale and large-scale systems exhibit the same hydrodynamic behavior.

Rambali et al. studied the top spray granulation of corn starch and lactose monohydrate using HPMC solutions in three fluidized bed sizes, with batch sizes of 5, 30 and 120 kg. They showed that the granulation process can be successfully scaled up by keeping the relative droplet size constant in each scale. Another scaling parameter called drying force, which represents the rate of evaporation of water from the granules, was defined by Hede et al. They conducted experiments in three different sizes of top-jet fluidized beds, with batch sizes of 0.5, 4 and 24kg, and concluded that for successful scale-up, the drying force and droplet size should remain constant at each scale. . The model tested different scaling-up principles by comparing simulation results with experimental temperature and humidity data obtained for placebo in 3 pilot fluidized bed scales. In some studies, more complex models are used.

02 Factors And Methods To Consider When Scaling Up

Fluid Dynamics Similarity

granule growth in a fluidized bed is closely related to the granule mixing and flow patterns in the bed. This dictates that the hydrodynamics of the scaled bed should be the same as that of the small unit, indicating hydrodynamic similarity. In a bubbling fluidized bed, bed expansion, solid mixing, granule entrainment, granule growth and abrasion are closely related to the movement of bubbles in the bed. There are several rules for amplifying bubbling fluidized beds under similar hydrodynamic conditions.

To ensure that the bed operates in bubbling mode without the risk of plug flow, the ratio in the above equation must be kept below 0.2. In addition, the ratio of bed height to bed diameter and the ratio of granule diameter to bed diameter should be kept low. For pilot fluidized beds, the diameter should be greater than 0.3m. The proposed similarity rule requires two conditions to be met. The first condition guarantees the similarity of bubble merging. The second method ensures the similarity of bubble splitting and interstitial flow patterns.

Fluidization Speed

In a fluidized bed, pressure fluctuations are directly related to the passage and bursting of bubbles. The speed at which the air flows over the distribution plate needs to be kept constant to ensure that the product fluidizes in a similar manner at different scales. The air velocity should be chosen so that it is above the minimum fluidization velocity of the largest granules and below the transport velocity of the smallest granules. The most uniform fluidization is likely to occur when all granules are approximately the same size, so there is not much difference in their final falling velocity. If the size difference is significant, segregation occurs and smaller granules are continuously lost from the system. If the granules forming the bed are initially of the same size, fines usually result from breakage due to mechanical wear or high thermal stress. Different bed heights do not produce any significant changes in the minimum fluidization velocity. Conversely, the density difference between materials affects the minimum fluidization velocity. Denser materials require higher surface gas velocities to begin fluidizing. Decomposition forces also increase with excessive gas velocities; therefore, the fluidization velocity is best set near the escape point of the smaller granules in the bed, thus ensuring vigorous fluidization at maximum bubble rates and thus minimizing the excess of large agglomerates Opportunity for segregation or defluidization.

Bed Moisture Content And Evaporation

granule growth in a fluidized bed includes three stages: nucleation, transformation and granule growth. The transition from the transition to granule growth regime depends primarily on bed moisture. The larger the unit, the greater the air flow and the higher the evaporation rate; it is necessary to maintain the drying capacity of the larger unit so that the bed temperature is the same as that of the smaller unit. This can be accomplished by increasing the spray rate, increasing air temperature, increasing airflow, or a combination of these variables to achieve suitable results. If the inlet air temperature and dew point remain constant, the increase in spray rate is proportional to the increase in air volume. The spray rate must be based on an increase in drying air volume, not an increase in batch size.

Bed Height And Weight (Volume)

As the height of the product bed increases, the mechanical stress on the material increases, which can lead to breakage of friable granules and therefore an increase in the amount of fines. Production equipment is usually designed to optimize bed depth and pot diameter. Breaking force increases with bed depth, so deeper beds are used for layer granulation or denser agglomerates (aspect ratio 2-3), while shallower beds are used for agglomerate growth (aspect ratio 2-3). Aspect ratio 0.5-1).

The determination of the scale-up batch quantity depends on the factory’s production equipment capabilities. To determine batch size, the bulk density of the product being processed should be known and can be calculated by knowing the volumetric capacity of the pot as follows:

Calculate the batch size (X).

If the pot size is 1100L.

The working capacity of the fluidized bed vessel is usually (range 50%-100%) 80%=0.8.

If the bulk density of the product to be processed is 0.4g/cc.

Then the batch size X can be calculated as X=0.8×1100×0.4=352kg.

When scaling from pilot batches to production batches, the increase in finished product bulk density is related to an increase in bed depth, typically around 20%.

When using a relatively higher height Wurster column for coating, the batch size and efficiency will be greatly improved. If a shorter Wurster column is used, the material will be dispersed prematurely, causing the coating material to enter the rising zone prematurely and cause spray drying.

Cross-sectional area

To maintain the product at constant humidity and temperature, the amount of process gas per unit mass of product and time should be similar for smaller and larger fluidized beds.

Drop Size

In order to reduce the scale-up production time, the liquid spray rate needs to be increased, so the atomization air needs to be increased to maintain the same ratio of liquid mass flow rate to air mass flow rate, thereby increasing the granule size of the granular product. These changes may affect granule size, but typically when granulation is scaled up, granule size increases due to mass effect. Changing the inlet temperature or atomization air pressure can have a synergistic effect on the granule size and bulk density of the product. Since the droplet size is a function of the mass ratio of air to liquid, its atomization capacity cannot be exceeded. If the spray rate needs to be increased, the atomizing air should be increased to maintain the same droplet size, but if there is not enough air volume for Atomization, then it is difficult to achieve a higher spray speed and maintain the same droplet size. Therefore, the droplet size should remain small relative to the original granule size. For a 5kg batch, the atomizing air pressure can be close to 40CFM, and for a 60kg batch, the atomizing air pressure can be close to 100CFM to maintain the same droplet size.

03 Scale-Up Of Fluidized Bed Granulation And Drying

The process factors that have the greatest impact on the granulation characteristics are the rate of addition of the binder, the degree of atomization of the binder liquid, the process temperature and the height of the nozzle from the bed. Since the ratio of bed depth to air flow distributor increases with the size of the equipment, the fluidization wind speed is kept constant by increasing the air volume. During the scale-up of a fluidized bed granulation process, a major factor that must be considered is keeping the binder droplets the same size to ensure successful scale-up. It is also important to keep bed moisture below critical moisture levels to prevent the formation of larger agglomerates.

Since the higher airflow and temperature (drying capacity) in the larger unit provide a higher evaporation rate, the bed temperature of the larger unit must be kept the same as that of the smaller unit, and the nozzles should be positioned to always cover the powder bed; therefore, the location and number of nozzle ports are also important considerations when scaling up.

The liquid spray rate and atomizing air pressure amplification can be determined by the drying capacity of the equipment, which is proportional to the cross-sectional area of the air distribution plate, rather than by the increase in batch size.

Additional Rules For Scale-Up Of Fluidized Bed Granulation

Granule size distribution and density do not change much when scaled up if the following rules are considered:

(1) The diameter of the fluidized bed unit of the pilot plant should be at least 0.3m so that bubbling rather than plunger fluidization behavior occurs. Bubbles of similar size and frequency are required in pilot and full-scale installations.

(2) Where possible, scale-up should maintain a constant fluidized bed height. Taller beds increase density and wear, requiring higher airflow.

(3) With the bed height remaining constant, the gas flux and solid capacity will increase as the bed cross-sectional area increases. Mass and energy balance limits should be checked when scaling up.

The nozzle type, droplet size distribution and relative nozzle position should be the same as the preceding unit.