How To Optimize The Fluidized Bed Process (Chapter 5)

Key Points Of This Chapter

The granulation process is actually about finding the balance point between spray and evaporation, as well as the relationship between particle growth and fluidization parameters. This seemingly simple process is not simple in actual application because, as mentioned before, pharmaceutical fluidized bed applications are still in a “blind box” state and lack dynamic methods to characterize the relationship between physical property changes and fluidization parameters.

Granulation is inseparable from binders. In addition to mastering the performance of equipment, we must also master the characteristics of binder excipients. Therefore, preparation workers are veritable “miscellaneous experts” who need comprehensive comprehensive capabilities to do a good job in the process. Evaluating adhesive efficiency is also necessary during process studies.

The nozzle/spray gun is the core component of the fluidized bed granulation hardware. It directly affects the degree of adhesive atomization, atomization intensity, and liquid spray rate. Choosing the appropriate nozzle/spray gun is particularly important in the granulation process.

The determination of the end point of granulation is very critical to the granulation process. Currently, there is no particularly effective method to directly determine the end point. Either the end point is determined by the amount of adhesive sprayed, or the end point is determined by off-line measurement of particle characteristics. The former is currently preferred.

Chapter 5 Granulation

01 Theory

Fluidized bed granulation uses a binary nozzle to spray a binder solution onto the fluidized particles and agglomerates the particles while evaporating the solvent. The success of particle aggregation depends on the amount of liquid on the particle surface and the strength of the liquid bridge between two particles. The particles are continuously mixed within the fluidized bed, and the fluidizing gas provides the necessary heat to dry and remove moisture. After stopping spraying, the remaining moisture evaporates during the final stages of drying until the desired moisture content is achieved. Fluidized bed particles are characterized by porous surfaces and high porosity. This results in liquid entering the granules more easily and improving disintegration or dispersion. In addition, due to these gaps, the volume density of fluidized bed particles is lower than that achieved by other granulation technologies (ps. But this is not absolute, and depends on the size of the fluidized bed, loading capacity, raw materials and binders etc.).

Wetting agent volume depends primarily on the solubility of the drug and/or excipients. Insoluble drugs require more wetting agents than soluble drug formulations. Particle size distribution, particle shape, surface roughness, as well as fluid, equipment and process characteristics all influence the wetting dose. Spray and evaporation, these two conditions must be in perfect balance to produce a normal fluidized granulation process (ps. This balance seems simple, but in fact it is difficult to control. The main reason is that the current gas-liquid process in the fluidization process The characterization of the solid three phases and other parameters is fragmented and there is no complete dynamic description. As a result, if the parameters we obtain can effectively correspond to the process and optimize the parameters, it is the difficulty of fluidized bed application); if it exceeds At any of these limits, wetting agent will accumulate in the bed, causing bed collapse or uneven product particles. The adhesive spray rate is one of the key factors in determining the particle size range.

02 Adhesive

Binders are an important part of the granulation process. The distribution of binder within the particles controls intra-particle adhesion and inter-particle compression. Most binders used in wet granulation are hydrophilic in nature. The type and amount of binder affects the average particle size of the particles, the hardness of the particles, the porosity between particles and the fluidity of the particles. The binder addition rate affects particle formation and particle size because it affects the degree of wetting and adhesive adhesion. Increasing the binder addition rate increases particle size and particle density due to increased penetration and wetting capabilities of the binder solution. Reducing the addition rate has the opposite effect, reducing particle size and density.

How To Choose The Right Adhesive?

Many parameters influence the properties of the particles, but the interaction between drug and binder plays a very important role. A number of techniques can be used to measure the wetting and spreading capabilities of adhesive solutions to ensure that the appropriate adhesive is selected for a specific substrate. Typically, this involves calculating surface free energy, as well as cohesion, adhesion, and diffusion (also known as diffusion coefficients) by measuring the solution contact angle on the substrate, and measuring the liquid-vapor surface energy of the wetting liquid (often called is the surface tension).

Indeed, once the compatibility of the binder and substrate is determined during pre-formulation screening, the challenge is to determine the percentage of binder required to form a bond between the particles. Binder efficiency can be defined as the minimum level of binder usage required to achieve a certain baseline tablet strength and brittleness. The hardness and brittleness of the particles generally cannot be determined until they are dried. Poor wettability and spreadability of adhesives are often associated with porous, weak, low-density particles, uneven adhesive distribution, and wide particle size distribution. The binder can be added as a powder to the fluidized bed loading chamber along with other ingredients, and a solvent (eg, water for aqueous granulation) sprayed to form the granules. But the bonds formed by dry adhesives are not as strong as those formed by adhesives in solution because it takes time for the polymer to hydrate. Therefore, it is recommended to use adhesives in solution. If most of the ingredients are highly water-soluble, it is possible to granulate the mixture in the bed by just spraying water; in this case, a lot of dry binder may be needed.

With weak or lower amounts of binder, the particles are brittle and unable to withstand the vigorous fluidization in the fluidized bed. On the other hand, if the amount of binder in the particles is too high, the aggregated particles will be too hard. This can lead to compression issues such as tablet spotting, too high hardness, and poor disintegration/dissolution. In addition to choosing an adhesive with lower surface tension, you can also add surfactants to reduce surface tension, or alternately add less polar organic solvents to the water, or replace the aqueous solution with less polar organic solvents. The properties of the adhesive (such as viscosity, diffusion coefficient, solubility, etc.) will ultimately determine the amount of adhesive used and the concentration required. The goal should be to use as much high concentration as possible in a state where it can easily atomize into droplets to minimize spray time while obtaining the desired particles, thus optimizing the process. Rajniak et al. studied the effect of binder properties on particle morphology and made qualitative predictions using a simple physically based criterion that combines the morphological properties of the excipient (size and surface roughness) with the physical properties of the binder ( viscosity, wetting properties, droplet size) combined.

03 Nozzle

The degree of atomization of the adhesive solution is controlled by the ratio of air to liquid mixture in the nozzle. The average droplet size is mainly affected by the nozzle structure, air mass ratio and dynamic forces of the atomized air, surface tension, liquid density and viscosity, and atomized air density. When the liquid orifice is wide enough to allow uniform flow, the diameter has no significant effect on droplet size. The height of the nozzle relative to the height of the powder bed within the fluidized bed cavity affects particle size and particle hardness due to over- or under-wetting. If the nozzle is too close to the fluidized material, it will disrupt the fluidization pattern. Due to overwetting, it can lead to particle agglomeration; worst of all, since fluidized particles are constantly hitting the nozzle, it increases the probability of nozzle clogging and process interruption. On the contrary, if the position of the nozzle is higher than the optimal level, the atomized binder droplets are spray dried before they have a chance to wet the fluidized particles, resulting in insufficient wetting, slow granulation speed or even no granulation. The nozzle position is set to evenly wet the “surface” of the bed, but not spray the inside walls of the container. Set the droplet size so that they reach the bed and are minimally dried or blowbacked.

(1) Different Directions Of The Nozzle

Top Injection: Since the 1960s, top injection granulation is one of the most recognized and well-researched fluidized bed granulation technologies. The particles produced by top spray granulation have the characteristics of low volume density and porous surface, which is conducive to the entry of liquid into the gaps of the particles, thereby facilitating the dispersion and disintegration of the particles.

Bottom spray: In order to adjust fluidization and prevent particles from flowing into the spray area, a partition column is often installed around the nozzle. The adhesive is sprayed in the same direction as the air flow. This method is mainly used for coating, not granulation.

Rotary and side spray: The purpose of this structure is to produce denser granules than general fluidized bed granulation. The nozzles are located on the sides of the fluidization chamber and are embedded in the powder bed during production. The rotating disk of the granulator provides centrifugal force which forces the granules towards the walls of the processing chamber. Fluidizing air is introduced through the slits, providing a vertical force that lifts the particles upward before gravity causes them to fall back into the disk. Since the particles formed are spherical, they are denser and less porous than the particles produced by the top spray structure. Rotary and side spray structures are suitable for producing granules that require coating.

Modification of the nozzle position: In addition to its own atomizing airflow, the binary spray gun has a protective airflow in the protective chamber. Double protection prevents the droplet-dense area from contacting the particles during high-speed spraying, effectively preventing adhesion; effectively ensuring adhesion. The atomization form of the agent/coating liquid is higher, and it effectively prevents the material from contacting the nozzle/lance head and prevents the material from blocking the gun. The air inlet of the chamber also adopts system circulating air, which effectively ensures the pressure of the entire fluidized bed cavity. drop).

Solution Delivery System: The type of solution delivery system used will depend on the adhesive used. Highly viscous liquids with high solids content may be better suited for positive displacement pumps. For solutions containing large amounts of solids, it may be better to use a gravimetric feedback system. However, most adhesives will work with mass flow rate systems.

(2) Nozzle Clogged

Keeping the nozzle free of clogging is a critical factor in the granulation process. Clogged nozzles during operation can cause atomization to deteriorate and may result in sudden over-wetting or over-drying. On startup, bed particles may be blown into the nozzle, or the liquid feed may evaporate in the hot nozzle. During operation, clogging may also occur due to evaporation within the nozzle. The ability to purge the atomizing port prevents nozzle clogging. Additionally, flushing the nozzle with pure solvent at the end of the run will ensure that no polymer or product remains in the nozzle.

The liquid to be sprayed must be free of clumps, which may block the flow of the liquid. Lumps or unhydrated polymer (fish eyes) account for a large proportion of all nozzle clogging in fluidized bed granulation. Blocks may also block one or more ports as they move out of the solution tank and toward the nozzle. Lumps that migrate to the nozzle port usually adhere to the interior and do not enter the fluidization chamber. Therefore, these blockages must be discovered and cleared as soon as possible.

In multi-port nozzles, the initial blockage of one port usually binds to the powder and migrates to the second (and possibly another) port. In other cases, after the solution hardens on the nozzle surface, it migrates downward and forms “whiskers” or “icicles.” Once the whiskers form, the solution form is immediately deflected downwards under the nozzle. This is usually evidenced by conical solution adhesion on the product bowl screen. Damaged “O” rings also often cause the needle valve to sit improperly, which can also have the above effects. It is also important to inspect the needle valve assembly regularly and replace damaged or worn O-rings as required. Frequent bag shaking during the spray cycle triggers a compressed air purge mechanism that also provides frequent solution jet purges. This is an effective measure to prevent nozzles from clogging. The nozzle atomizing pressure actually assumes that the nozzle also receives the required mass flow rate of air. If the pressure is monitored near the nozzle, then the mass flow rate of the atomizing air is most likely correct. However, this ignores the fact that the nozzle tip is not clean and the nozzle is not functioning properly.

04 End Of Granulation

(1) Offline Method

Fluidized bed granulation is dynamic and measurement of the granulation endpoint is difficult. After drying is complete, the true end point and particle size determination are apparent. Particles formed during binder spraying may or may not be retained. Whether it is retained in the form of particles depends on the quantity and mechanical strength of the binder, as well as the strength of the bonds formed during the spraying stage. In determining the end point, particle porosity, flow characteristics, density and particle size distribution are key characteristics and should be used as criteria for completion of the process. The end point of the granulation process is determined based on the amount of binder liquid added as primary particles agglomerate. Typically during the product development phase, the quality of the final particle properties is determined. The amplification process needs to be powerful enough to be able to expand the amount of adhesive liquid. The quality of granulation is usually assessed by laboratory analysis of selected samples for critical quality attributes. A more effective way to control the granulation process includes real-time product quality assessment, supplemented by real-time process parameter adjustments to correct undesirable changes in product performance and process progress. This requires the development of automated granulation processes that use in-line equipment to directly measure key product parameters.

(2) Near Infrared

Moisture content and particle size determined by the near-infrared monitor correlated well with those measured offline. Given a known recipe, with predefined peak moisture content, final moisture content, and final particle size parameters, a near-infrared monitoring system can control the fluidized bed by determining when binder addition should stop and when particle drying is complete. Granulation. Near-infrared (NIR) spectroscopy has broad application prospects in measuring particle size due to its cross-sensitivity. Through chemometric modeling, particle information can be extracted from baseline shifts and slope changes in the near-infrared spectrum. Some studies have shown that combining near-infrared moisture information with traditionally collected process parameters adds granulation information, improves model predictability, and helps process optimization. The challenge with this online technique is that the measuring device is in a fixed position while the particles fly throughout the fluidization chamber. There are few commercially available in-line particle size measurement technologies during wet granulation processes. The use of diode ray detectors for near-infrared measurements has recently been introduced. It prevents probe fouling. The diode array detector in the device can acquire spectra in milliseconds by averaging these spectra over time to adjust the measured product volume to the volume typically used in offline measurements.

(3) Focused Beam Reflection Measurement (FBRM)

Focused beam reflectometry (FBRM) instruments are designed to track any changes in particle size and their distribution in real time. The FBRM probe scans with a focused laser beam in a circular path at high speed (2-8 m/s). Particles passing in front of the measurement window are hit by the laser, causing the laser light to scatter in all directions. Use backscattered light to calculate particle chord length and particle chord length distribution. Online FBRM applications show particle growth kinetics, but fouling that may be observed in process measurements hinders the reliability of the FBRM technology as an online process analyzer. To address these fouling issues, the probes were adjusted. The FBRM C35 probe is equipped with a pressurized pneumatic mechanical scraper over the sapphire measurement window to prevent powder adhesion.

(4) Spatial Filtering Velocity Measurement Method (Parsum)

In addition to FBRM, spatial filter velocimetry (Parsum) can also be used to measure particle size. The Parsum probe adopts the measurement principle of spatial filtering velocimetry. This is a numerically based chord length quantification method that collects data on individual particles to obtain particle size distribution and velocity distribution. Particles passing through the measurement area of the Parsum probe block the light from the laser source. The resulting shadows are detected using a linear detector array consisting of optical fibers. Jun Huang et al. used Parsum probes to evaluate manufacturability quality attributes, particle size, and particle size distribution for online monitoring.

(5) Imaging Method

Images provide direct information about particles. The image analysis process includes five steps: image acquisition, preprocessing, segmentation, extraction and feature parameter representation.

05 Particle Characterization

(1) Fragility

Abrasion resistance or friability is used to evaluate the strength of particles. The brittleness test was used as the change in average particle size before and after the test, and the brittleness index (FI) was numerically calculated. FI is a parameter that defines a single point. However, during the sieving and mixing after the drying process in the industrial manufacturing stage, the brittleness events of the particles appear as a temporal continuum. There is currently no official procedure for testing pellet fragility.

(2) True Density

Measure true density using a helium concentration meter. Results are the average of five replicate determinations.

(3) Bulk Density

Gently place the sample into a 100ml graduated cylinder to the 100ml mark and weigh. From the mass and volume data, the bulk density is calculated. Results are the average of triplicate determinations.

(4) Tap Density

The same sample used for bulk density measurement can be passed through a tap density tester with a displacement amplitude of 14mm and 1500 taps. Results are the average of triplicate determinations.

(5) Measurement Of Flow Characteristics

Flow testers measure flow rate by weighing the same number of friable and non-friable particles each time. The dynamic angle of repose method was used to determine the angle of repose of brittle particles and non-breakable particles.

06 Summary

Fluidized bed granulation is a critical unit operation. Understanding the equipment, capabilities, and limitations of each component is essential to developing a fluidized bed granulation process. The interaction of process variables creates a dynamic environment in which the quality of the particles produced depends on the fluidized bed process parameters as well as the nozzle operation and binder used.