How To Optimize The Fluidized Bed Process (Chapter 9)

Chapter 9 Other Processes And Applications Of Fluidized Bed

01 Introduction

Over the past 50 years, fluidized bed processes have evolved from simple drying units to granulation, coating and various other application technologies. Notable among them are: the use of low-melting point waxes and polymers for granulation in fluidized beds; the use of steam-influenced aggregation (PSG) to produce instant granular products and bitter drug taste masking. The fluidized bed process has advantages in producing modified release forms, increasing solubility, changing density, and masking the bitter taste of oral solid dosage products by manipulating formulation or process parameters.

02 Fluidized Hot Melt Granulation (FHMG)

Melt granulation is a hot-melt technology and is an alternative to the classic solvent-mediated aggregation process (ps. Classic solute-mediated is wet granulation using a solvent as a wetting agent or binder). Melt granulation is an emerging technology based on using a binder with a relatively low melting point (between 50 and 80°C) and acting as a melt binding liquid, or combining a low melting point binder with a powder and using a fluidized bed of hot air The binder is melted, effectively acting as a liquid binder to prepare the pellets. Applying this method can also produce solid dispersions of poorly soluble drugs to improve solubility and bioavailability. The main advantage of the hot melt process is that it is solvent-free and can be effectively used to enhance the chemical stability of moisture-sensitive drugs and improve their physical properties. Furthermore, the drying stage is eliminated, making the process more economical and environmentally friendly. There are also some limitations to using the melt granulation process. Melt granulation or thermoplastic granulation is the aggregation of binder materials that are solid at room temperature but soften and melt at higher temperatures (i.e. 50-90°C). When melted, the binder liquid acts similarly to a wet granulation process. The binder is added in powder form to the starting material at ambient temperature and the binder is heated above its melting point (in-situ granulation) or sprayed in molten form onto the heated material in a fluidized bed (spraying liquid granulation).

In the in-situ granulation process, molten materials and other powders are added to the fluidized bed and the inlet temperature is set to an appropriate value to initiate granulation by melting the binder. The system is cooled to a solid state and the molten excipient acts as a binder. For liquid spray granulation, the meltable binder is heated and the liquid binder is held above the melting point of the binder until sprayed through a two-fluid nozzle. The pipes carrying the molten adhesive also require heat tracing (heating) because the atomizing air is at a high temperature to avoid cooling the adhesive as it exits the nozzle. When the end point of granulation is reached, the materials in the fluidized bed can be quickly cooled by fluidizing air. In either case, the process temperature should be adjusted to avoid solidification of the adhesive prior to granules/pellet collision. By adjusting the binder addition rate and the amount of powder passing through the spray zone, the probability of granules/binder collisions can be increased. In addition to the amount of binder, agglomerate growth during fluidized hot-melt granulation (FHMG) also depends on the viscosity of the molten binder. Overall, the most important key variables that determine granules size and granules quality during FHMG are concentration of binder, viscosity, spray rate and droplet/granules size, primary granules size, bed temperature, atomization pressure, air velocity, and fog chemical pressure. However, melt granulation is less sensitive to the amount of air in the fluidized powder bed than wet granulation. In wet granulation, the liquid evaporation rate is determined by the air flow rate, and the spray rate must be sufficient to exceed the drying rate caused by the air flow to ensure agglomeration and consolidation of the granules during processing. Since no evaporation of the liquid phase occurs during melt processing, the effect of this variable is eliminated.

The main disadvantage is the high temperatures required during this process, which may lead to degradation and/or oxidative instability of the ingredients, especially for thermally unstable drugs. Binder viscosity was shown to significantly affect granules growth; it can be concluded that a low-viscosity, high-flow molten polymer will be produced through coalescence and continuous growth, while a high-viscosity binder will cause the system to separate in the powder. The layer cannot grow after it occurs because the binder cannot migrate to the outer surface of the colliding granules. Kukeca et al. showed that melt granulation using hydrophilic binders is an effective method to increase the dissolution rate of poorly water-soluble drugs. The binder addition procedure affects the dissolution curve obtained from FHMG produced pellets. The spray procedure resulted in a higher dissolution rate of carvedilol from the granules. FHMG has been proposed as a way to mask the bitter taste of drugs. Waxy binders have been used to prepare regular and extended-release tablets and, more recently, rapid-release tablets. Yanze et al. reported a method for preparing effervescent granules using fluidized bed melt granulation using polyethylene glycol (PEG) 6000 as a melt binder. The laboratory studied the melt solidification technology for preparing sustained-release ibuprofen using cetyl alcohol. Likewise, other waxy carriers such as beeswax, carnauba wax, microcrystalline wax, presirol ATO5, and glyceryl ester 64/02 have been studied in the preparation of microspheres. Extended-release ibuprofen mini-tablets have been prepared by melt extrusion technology using microcrystalline wax and starch derivatives. To obtain tablets with a disintegration time of less than 10 minutes, add 2.0% crospovidone as a disintegrant. The use of the FHMG method resulted in tablets with faster carbamazepine solubility (more than 80% of the drug released within 15 minutes) compared to tablets prepared from wet granule clusters. This is achieved using mannitol or lactose/microcrystalline cellulose as fillers. Zai et al. used the FHMG method to prepare gastric retention sustained-release floating granules. Floating granules are released continuously for more than 10 hours. Drug release and flotation properties can be controlled by changing the ratio or physical properties of the excipients used in the formulation. FHMG improves the stability of enalapril maleate. The obtained granules showed fluidity and rapid dissolution rate of enalapril maleate, releasing almost 100% of the drug within 10 minutes.

03 Spray Condensation

This process, also known as spray condensation, is a melt granulation technique in which solid granules are dissolved or dispersed in a molten carrier (with a melting point above room temperature) and the resulting liquid is formed at a temperature below the melting point of the carrier (i.e., typically at ambient temperature Bottom) Atomized in a chamber, the molten carrier in the droplets condenses when it contacts the colder airflow in the spray condensation device, quickly forming solid spherical granules. The spray condensation process involves spraying a hot melt adhesive of wax, fatty acid or glyceride into an air chamber at a temperature below the melting point or cryogenic temperature of the meltable material. After cooling, granules with a diameter of 10-3000 μm are obtained. Since no solvent evaporates, the condensed granules are strong and non-porous. Based on its working principle, spray condensation is related to spray drying as traditional melt granulation is related to wet granulation. Depending on the carrier material, this technology can prepare sustained-release granules for oral drug delivery, increase the dissolution rate of poorly soluble drugs (even without forming a solid dispersion) and mask the taste of the drug.

However, the main limitation of spray condensation is the difficulty in achieving drug loadings above 25% because the formulation must be pumped to the nozzle and atomized in the cooling chamber. At higher drug loads, molten formulations are often too viscous to obtain non-agglomerated spherical granules with a narrow size distribution after atomization by pneumatic two-fluid, rotational (or centrifugal) or ultrasonic-assisted nozzles. Pressure nozzles are less commonly used for spray condensation because the high viscosity of the formulation requires excessive pressure.

From a processing perspective, the size of the cooling chamber must be sufficient to ensure high throughput, so when high production capacity or large granules are required, a large spray condensation tower may be required. Additionally, the cooling chamber needs to be sized based on the type of nozzle being atomized and the trajectory of the granules; rotating nozzles require wider chambers, while dual-fluid nozzles can be combined with taller but narrower chambers to optimize process throughput. Therefore, it is more economical to use a spray dryer to produce spray condensation.

04 Variable Pressure Granulation (PSG)

PSG uses pressure to agglomerate powder in a rotating fluidized bed without the need for any binders. In PSG, the powder bed is fluidized in one cycle and compacted in another cycle. This helps form spherical granules without any binder. Dry coating, which attaches tiny submicron granules (coating) to relatively larger micron granules (host) without the use of any solvents, binders or even water, is a promising alternative method.

PSG technology utilizes the spontaneous agglomeration properties of viscous fine powders or Geldart Group C powders. In the PSG fluidized bed, fine powders are granulated by circulating fluidization and compaction, carried out by alternating upward and downward air flows. During compaction, the sharp spike-like pressure reversal created by opening the valve in the upper pressure chamber returns the fine granules collected by the bag filter back into the bed, simultaneously destroying the channels in the bed. The compaction process and the granulation-fluidization process are repeated in turn. During the compaction process, gas flows from the upper side to the lower side and the powder bed is completely compacted. During the granulation-fluidization process, bubbles rise through the powder layer, and the powder granules are forcibly compacted in the granules-thick region formed below the bubbles. As these processes are repeated, granules are formed primarily by van der Waals forces. The PSG method can create granules composed of pure drug granules. Fitrah et al. used PSG to produce ibuprofen and lactose granules using gas at 70°C in a 3:7 ratio, eliminating the tendency to stick during tableting. Masayuki Watanabe et al. granulated agglomerates of sodium salicylate powder (sodium salicylate and calcium gluconate) via the PSG method for the preparation of granules for inhalation.

05 Wuster Module For Granulation

Top-jet fluidized bed granulation is currently the gold standard in the industry. Bottom jet fluidization technology, also known as the Wurster process, is mainly used for coating and less frequently for granulation. In the Wurster process, the granulation liquid is atomized and sprayed directly onto the suspended granules which are supported by an air flow and move upward. Based on the Wurster process, Ichikawa and Fukumori proposed the concept of microagglomeration, which converts powder into agglomerates of 20-50 μm size and then microencapsulates them through film coating. Rajniak et al. used 15% binder solution to granulate mannitol, A-tab and Avicel. The resulting granules were more evenly distributed and had a tighter granules size distribution. The Wurster process is also used to produce pellets by layering a solution or suspension of the active pharmaceutical ingredient (API) onto an inert core (microcrystalline cellulose or sugar spheres, etc.) or crystals of the API, which is then coated with a polymer. Clothing to modify release properties.

A modification of the Wurster process is called a precision granulator, which uses an improved air distribution pattern to improve the fluid dynamics of the system. A high-speed and rotating airflow is established in the central tube. The granules are collected at the bottom of the tube and accelerated by the air flow. The granules come into contact with droplets produced by a nozzle at the bottom of the tube. Within the central duct, the relative velocities of air, droplets, and granules are high, the wetting efficiency is high, and drying begins almost immediately. The agglomerates are dry by the time they leave the top of the tube. The materials are not fluidized; they are conveyed pneumatically by air flow. Therefore, air velocity is not as critical as in fluidized bed equipment. The highly ordered granules circulation pattern and unique hydrodynamic properties in precision granulation facilitate wet granulation of moisture-sensitive and low-dose drugs. Liew and colleagues demonstrated the suitability of precise granulation for soluble, viscous or hygroscopic materials. They compared the performance of granules produced by precision granulation, top spray granulation and high shear granulation on an industrial scale and found that the porosity, strength and density of granules produced by precision granulation were intermediate between those produced by top spray granulation and high shear granulation. Cut between granules. At the same tablet weight and hardness, tablets produced by precision granulation have shorter disintegration times.

06 Foam Granulation

Foam granulation technology was developed by The Dow Chemical Company. This technology enables faster granulation, which involves a simpler wet granulation of the material and the use of a high-shear mixer, or fluidized bed processor. Foam technology involves making a foam of a binder, such as hydroxypropylcellulose, and adding it to a powder to form granules. Foam adhesives have a high spread-to-dip ratio. The granules are sprayed rather than soaked, distributing the adhesive more consistently and placing the adhesive where it needs to be: on the surface. Since no nozzles are involved, it eliminates all nozzle-related variables (nozzle configuration, distance from moving powder bed, nozzle plugging, spray pattern, droplet size and distribution, etc.). Less water is required for condensation and evaporation, resulting in shorter production times. The research and application of foam binders in high shear granulation are increasing in industry, but their application in fluidized bed granulation is not yet widespread.

07 Steam Granulation

The technology is a simple modification of the traditional wet granulation method, in which steam is used as a binder instead of water, and involves injecting a steam jet into a fluidized bed of granules to be granulated. Pure steam is a transparent gas, providing higher diffusion rates and a more favorable thermal balance during the drying step. After the steam condenses, the water forms a hot film on the powder granules that requires only a small amount of additional energy to remove and makes it easier to evaporate. Advantages of this process include a higher ability for uniform distribution and diffusion of vapor into the powder granules, production of spherical granules with a greater surface area, thereby increasing the rate of drug dissolution from the granules, and good thermal balance resulting in rapid drying and shorter processing time. However, this process also has some disadvantages. The key is that it is not suitable for hot-melt APIs and is not suitable for all binders. It requires special equipment for steam generation and transportation, and since the steam temperature is about 150°C, it is locally overheated. Excessive wetting of granules near the nozzle can cause agglomeration. Sotome et al. used a steam/water two-step technique to granulate food powders in a fluidized bed. For the mixed powder of corn starch (800g) and dextrin (200g), superheated steam and water (127°C, 138 kPaG) are sprayed through a single-fluid nozzle at a speed of 18.8g/min and 0 ~ 40g/min, respectively, and sprayed onto the powder. The amount of water is reduced to 40%-84%, and the resulting granules size is comparable to conventional fluidized bed granulation using a liquid binder.

08 Rotating Fluidized Bed Granulation

Rotor technology is a “single pot” granulation and dense granule production method based on fluidized bed technology. Different equipment manufacturers have different designs, but the basic concept is the same. The perforated air distributor of a conventional fluidized bed is replaced by a rotating solid metal disk. By raising and lowering the disc, the space between the edge of the disc and the wall of the container can be changed, and the airflow can be adjusted. The material being processed in the rotor module is subjected to the combined forces of centrifugation and fluidization. Rotor technology has been used to produce denser granules. Robinson and Hollenbeck have reported the use of rotor processors in the production of spheroids. In a single-step procedure, the entire operation of sphere formation, drying, and coating may be restricted to a single piece of equipment. Spheres are formed directly from materials in powder form through an aggregation-spheroidization process. Powder handling capabilities required modifications to the spheronizer chamber. Positive pressure must be maintained between the annular gaps to prevent powder sliding between the friction plates and the rotor housing. One of the advantages of rotating fluidized beds is better mixing and coating of granules and the possibility of obtaining spherical pellets and granules from powders. During the binder solution injection process, the flow is tangential and co-current, making the material distribution more uniform.

The surface and rotation speed of the disc have an impact on the shape, surface and size of the granules, but have a smaller impact on density, moisture content and yield. During the agglomeration process of powder granules, keeping the rotation speed of the smooth disk constant and increasing the rotation speed during the spheronization process of the agglomerates can result in more spherical granules, larger diameters, and smoother granules surfaces.

Granulation in a rotary processor using polyethylene glycol (PEG) solution as the primary binder liquid was found to be a robust process. This process can be used to prepare agglomerates with high drug content and physical properties suitable for further processing, such as coating, capsule filling, or compression. This process allows the incorporation of up to 42.5% wt/wt PEG and therefore can be used as an alternative to melt granulation of hydrophilic meltable adhesives.

Another advantage of rotating fluidized beds is the ability to layer powders onto substrate granules. The rotor requires some modifications to feed powder into the rotating granules or pellets in a consistent manner and to spray the binder solution tangentially. When the granules become wet, the powder sticks to the granules and due to fluidization they are quickly dried. Caroline Désirée Kablitz et al. developed a process in a rotating fluidized bed with a three-way nozzle and a gravimetric powder feeder for optimal coating material application using hydroxypropyl methyl fiber succinate. Acetate ester is used to obtain enteric coatings without the addition of talc as an anti-sticking agent. This process is an efficient process, the coating stage only takes 23 minutes, the curing stage only takes 45 minutes, and the energy consumption is low.

09 Spray Drying Granulation

The spray drying process involves atomizing a pumpable liquid, solution, suspension or slurry. A typical spray dryer consists of a chamber, an atomizer wheel or nozzle, a pump and a source of heated gas (for drying the millions of droplets formed), a dry powder collection container, and a dryer to separate the air and fine powder escaping the device. Cyclone separator as well as a secondary filter to capture fines or in some cases a scrubber if an organic solvent is used as the carrier liquid. Spray dryers are configured as closed or open circulation units, depending on whether the solution/suspension contains organic solvents or water. It is a continuous process in which a dry product is obtained by feeding a solution or active agent suspension with or without excipients to a drying system, where the feed is atomized and dried with a heated air stream and subsequently separated from the air stream Powder/granular products.

Spray drying is a unique process compared to other granulation methods. A solution/suspension is a homogeneous liquid, resulting in an even distribution of all components. Many granulation methods utilize mechanical energy in spray drying to produce granules; unlike high-shear granulation processes, the product is affected by shear forces. When using nozzles or centrifugal atomizers, the energy transferred therefrom does not adversely affect the granules formed. The active pharmaceutical never comes into contact with any moving parts within the spray dryer; therefore cleaning issues are minimized.

The simplicity of the spray drying process and its ability to control the granules size of the resulting powder opens up the possibility of using spray drying technology to produce directly compressible “roller hopper” granulations. Ibuprofen and acetaminophen granules are manufactured using a spray dryer and are formulated to contain the drug, microcrystalline cellulose and other suspension excipients; the resulting granules display ideal flow and compressibility when compressed in tablets. By using a spray dryer, many of the unit operations involved in producing tablets or capsule granulations are eliminated. There are reports in the literature that improving the compression behavior by changing the crystal properties of acetazolamide.

10 Continuous Granulation

Continuous processing has long been supported by the FDA (U.S. Food and Drug Administration), which has been interacting with the European Medicines Agency and is consistent with the FDA’s Process Analytical Technology (PAT) and process validation guidance. The term “continuous” applies to all production or manufacturing processes that operate in a continuous flow. According to this definition, continuous processing of solid dosage products in the pharmaceutical industry means starting the process from API synthesis to final packaging of tablets or capsules 24/7, all year round. In the 1980s, Koblitz and Ehrhardt reported continuous wet granulation and drying. This article focuses on continuous variable frequency fluidized bed drying. In an article in Manufacturing Chemist, Berkovitch cited some researchers presenting these concepts at a workshop. Kawamura also discussed continuous processing of pharmaceutical products, including solid oral dosage form manufacturing processes.

Drivers for continued production in the pharmaceutical industry include new chemical entities becoming increasingly more potent/toxic. Small dedicated suites are suitable as “containers” for powerful medications. Investment costs for multi-product facilities for high potency oral solid dose products are inflated due to segregation measures. FDA initiatives and recent offerings of compact integrated systems from equipment and software vendors continue to drive this progress. Operational and labor savings for high-volume products can be an important driver.

Continuous granulation in a fluidized bed is more common where large quantities of product are required. Current interest in continuous granulation focuses on combinations of high-shear/twin-screw extruders with continuous dryers. Below are some systems offered by equipment vendors.

GEA Pharmaceutical Systems offers the “Consigma” integrated granulation/drying and tableting system. Based on twin-screw wet granulation and fluidized bed drying, the integrated system is capable of producing 0.5 to 200 kg of product depending on the size of the system. In twin-screw continuous wet granulation, powdered solids and binders are passed through a twin-screw extruder, usually with a rotating screw. The resulting granular product is continuously dried, ground, mixed and compressed.

Many unit operations are sequential in nature and easy to understand. The equipment is available for all remaining unit operations. The experience with continuous wet granulation has been positive. Opportunities exist to adopt continuous processes based on a quality-by-design approach, which will require simpler process analysis systems and more advanced control systems. It is important to recognize that not all products or processes will be produced using continuous granulation methods. Each API must be evaluated for its ability to be a candidate for continuous granulation, and associated processes must be developed for this purpose.

Bohle offers BCG systems with a twin-screw structure. Granulation was performed using a twin-screw extruder, and drying was performed using infrared and vacuum. The processing capacity of 8-30kg/h is controlled by the dosing device. Residence time varies based on required throughput and desired product attributes.

Glatt Pharmaceutical Systems offers continuous granulation systems where the product is granulated in a continuous fluidized bed granulator/dryer. The composition to be granulated is fed at one end of the device, the binder liquid is added to the product as it flows through the fluidized bed device, and granulation and drying are continued until the dry product is discharged.

Loedige offers a continuous granulation system in which a pre-mixed composition is fed into the system and, at very high rotational speeds, the product is moved as annular layers through horizontal rollers. The addition of liquid is done by an injector or through a hollow shaft. The granulated product is then fed into a continuous fluidized bed dryer with varying fluidization speeds as the product passes through the dryer and is further processed as required.

At the time of writing, the US FDA has approved two products using continuous manufacturing. However, process understanding and a sound risk management plan in continuous manufacturing will be key to successful implementation. Continuous manufacturing approaches must be viewed as process development platforms enhanced by continuous manufacturing. Continuous manufacturing provides new attention to process analytical systems, process control, and online instrumentation. Implementation of continuous processing will be based on how manufacturers overcome challenges in compliance, process design, process control and ultimate quality.