Choosing the Perfect Granulation Set-Up

When manufacturing solid dosage forms, such as wet and dry granules for compression, effervescent granules, or (micro) pellets for the pharmaceutical, homeopathic, and food supplement industries, several criteria are significant when choosing the right manufacturing process. In addition to the requirements for the quality and quantity of the granules and their particles, the specific handling requirements of the respective active ingredients and excipients in terms of toxicity and sensitivity to factors such as light, moisture, heat, and oxygen, play an essential role. Finally, external factors such as budget requirements, space requirements, the need for flexibility regarding product changes and process options, efficiency (downtimes and process speed,) and staff availability are also critical. The article gives a short overview of common batch granulation techniques and compares different process options in the context of various criteria such as particle shape, size, distribution, and more. Process analytical technology options, that enable monitoring and ensuring product quality in real-time is are also discussed.

Thus, the article intends to provide a decision-making aid for the right wet granulation manufacturing process.

Wet Granulation Processes

In pharmaceutical manufacturing, the primary objective of granulation is to create a stable dosage form. Therefore, the objective of a granulation process in oral solid dosage (OSD) manufacturing is to obtain a mixture with desired properties for subsequent steps such as pelletizing tableting, or coating. Components can include fillers such as lactose, cellulose, or mannitol; binders such as starch, or povidone; or disintegrants may be incorporated into the mixture in addition to the active ingredient.

Wet granulation can enhance flow behavior and compressibility, augment bioavailability, and facilitate greater homogeneity. An optimal system configuration with precise process analytical technology (PAT) makes wet granulation efficient and addresses challenges with the active ingredient or formulation.

The granulation process typically consists of a series of steps, including:

1. Mixing the raw materials
2. Spraying the granulating agent to disperse the liquid in the mixture
3. Building bridges between individual particles in the granulation phase. Particles are then compressed until the granulate, or snowball-like structure, is formed.

Depending on the targeted pharmaceutical product and its characteristics like the release and dissolution profile (e.g. standard tablet, effervescent tablet or pellets, powders, pellets of compression or encapsulation, etc.) as well as handling requirements granules must have specific properties e.g. type of fines content, particle shape, density, particle size distribution (PSD) are required.

There are several processing options for wet granulation and drying, each achieving specific granule characteristics. These technologies also differ in possible process range, degree of containment options, efficiency, flexibility, investment costs, space requirements, etc.

The following batch process options will be discussed:

• High-shear granulation plus several drying options
• Fluid-bed processing
• One-pot systeAndnd compared according to the criteria listed:

• Product Quality
• Flexibility
• Willingness to invest
• Space requirements

High-Shear Granulation Plus Drying

The high-shear granulation process is a well-established method for producing moist granules, which are subsequently dried. There are several ways in which mixer granulators can differ and these can affect a number of factors, including the quality of the granules, the mixing speed, homogenization, and cleaning.

An optimized high-shear granulator (HSG) bowl ensures homogeneous mixing and granulation of powdery raw materials. A precisely formed, bottom-driven mixing tool and an effective chopper placed in a conical-cylindrical shaped vat provide exceptionally good mixing results within just a few seconds and homogeneous moist granules. It also prevents product loss compared to the most top-driven variants. The moist granulate must then be dried — for example, in a tray dryer (TD) or a fluid-bed processor (FBP).

The different methods produce different results regarding respective granule properties.

• Fines content: The quality of the dry granules in combination with the TD has a higher proportion of fines, whereas the combination of an HSG with the FBP results in low to medium fines content.
• Density: The granulate density ranges either in the high to medium (TD) or in the high range (FBP).
• PSD: The Gaussian curve of the particle size distribution (PSD) is medium-ranged (HSG + FBP) or rather wider (HSG + TD).
• Shape: In terms of particle shape, HSG + TD achieves round to irregular shapes whereas HSG + FBP reaches rather round shapes.

The compressibility is good in both. Quantitatively, the yield is exceptionally good. The average product loss of the HSG + TD combination is around 1-3% slightly lower compared to the HSG + FBP variant, which is around 2-3%. However, the processing time in the HSG + TD combination is ≥ a factor of four in comparison to the combination of the significantly more efficient HSG + FBP processing. The absolute investment costs are correspondingly lower in the less efficient variant, but higher in productivity (costs per batch) compared to this and all other following processes discussed. Finally, high-shear mixers can be used for a broad range of materials and allow for several other process options like dry mixing (HSG), hot-melt granulation, and pelletization (with a respective spheronizer attachment); the combination with an FBD offers additional options like pellet coating in the FBD with a Wurster-Tube (bottom spray). The integration of an extruder completes the equipment to a pellet line.

High-shear granulation With Carrier Gas Vacuum Drying (One-Pot System)

The one-pot or single-pot system allows mixing, granulating, and drying in just one machine. Drying takes place under a vacuum. As the applied vacuum lowers the boiling point of the product less energy is required for heating. Drying can be initiated automatically after the granulation process. The dry granulate has a medium to high proportion of fines compared to the other methods and the granulate density is high. A medium to wide PSD is achieved, and the particle shape is round.

The fine content is in the medium to high range. Quantitative terms are very positive with a yield of >97%. The absolute and batch-related investment costs are in the medium range compared to the other methods (except for HSG + TD). Virtually all materials can be converted in the single-pot processor, and it is particularly suitable for solvent-based processes and environmentally sensitive products (e.g. effervescent granules). The advantage of a near-to-zero product loss makes it very suitable for expensive solvents and raw materials.

Further processing options are hot melt granulation and dry mixing.

Fluid-Bed Granulation

A fluid-bed processor allows mixing, different granulating options, and drying. Granulation takes place without mechanical force by spraying the fluidized product with binders. Compared to the high-shear method, the granule's shape is more porous and has a raspberry-like structure as well as a reduced particle size and bulk density. The PSD is somewhat more homogeneous and narrower.

The texture leads to improved dispersibility. Granulation can be carried out in two ways. In top-spray granulation, the spay application takes place above the product bed, in counterflow to the drying air. This results in higher spray drying losses compared to tangential spray granulation, in which the spray is applied laterally and directly in the product bed near the air distributor.

The spraying time can be reduced by around 30% by tangential spray processing while the spraying rate increases by around 30%. Despite these and other advantages, the top-spray application is still the most common of the two variants. Regarding the range of applications, it should be noted that fluidized bed granulation is not suitable for voluminous or cohesive base materials. Besides the further processing option of pure drying of moist raw materials, all other options are already stated above.

Process Analytical Technologies

For a more precise and efficient production (or development) quality-compliant process analytical technologies can be used. The main advantage of PAT is that it allows for measuring the state of a process without physically disturbing it by taking samples. It enables a timely characterization and analysis of raw or in-process materials by assessing their critical quality attributes in real time. Methods such as near-infrared (NIR), a spectroscopic method for in-line API quantification during fluidized bed granulation, belong to the range of PATs.

Most equipment suppliers also deliver PAT equipment and opportunities. A basic feature of a DIOSNA High-Shear granulator is comprised of software and a variety of measuring parameters. The validated program is capable of calculating a range of data and key figures derived from the measured values like temperature, the peripheral speed of the mixing tool, Froude number (needed for scale-ups), active power, total energy consumption, torque, and power curve inflection point. Should the adjustable maximum values for power and torque be exceeded, warnings or alarms are triggered, thereby advancing the mixing program. These values are used to determine the endpoint of the granulation process. To ensure product quality a probe allows detecting the particle size distribution inline, providing measured values in real time.

Machines can be prepared for the integration of a probe by analyzing further parameters like PSD, particle density, humidity, shape, etc.

PAT for FFBD includes options for the measurement and control of the inlet and exhaust air including temperature, volume, pressure, humidity, and more. Furthermore, the material bowl of the fluid-bed batch processor is prepared for NIR in-line-product moisture measurements, in-line detection of particle size, density,y and distribution, and more combining process and product analytical tools.

Investment

In general, the aim of the manufacturing industry is economic efficiency. Some critical points are among others:

• High-priced active ingredients & excipients
• High-priced solvents
• Investment costs
• Productivity costs
• Downtimes

Regarding the absolute investment costs, the combination of a mixer-granulator with a tray dryer wins the race. This variant is a good choice for handling inexpensive materials that require simple handling and a medium level of productivity. There are no containment options, and the environment as well as surroundings can influence the processes. Processing is simple and compared to the other methods only a little space is required in the technical zone.

The investment costs are highest for the combination of a high[1]shear granulator and fluidized bed dryer. On the other hand, the process flexibility is the greatest. So, if you want to use several process options — mixing, wet granulating, drying, granulating, pellet coating — this is the right choice for you, and there is also a variety of options in terms of granule quality, as described in Table 1. The flexibility is also reflected in the cleaning process. All individual process units and their surroundings must be cleaned, but this can be done alternately. This applies to non-containment operations.

Single-pot processors offer the highest product yield and even sticky materials can be processed very well thanks to an integrated wall scraper. The impeller is installed at the bottom of the mixing container, and a chopper is also attached vertically from the lid. These three factors lead to very good mixing and granulating results with excellent heat transfer and a particularly high product yield. It is ideal for more expensive products. Solvent recovery, such as methanol, can also be easily carried out using a condensate collection container. The flexibility in terms of process changes cannot be compared with the HSG + FBP combination. The quick and easy cleaning makes both processes immediately available. Even after containment applications, which are easier to use in a one-pot system.

Overall, processing in just one system reduces the incidence of errors compared to implementing different process steps in different devices. Fluidized bed granulating offers a similar advantage in this context. This is because space is only required for one device. Also, a lower ceiling height is required. The investment costs for the single-pot processor lie between the other two granulator combinations (+TD and + FBD). It requires fewer personnel for operation and cleaning.

Conclusion

Solid dosage forms are widely used in various industries, such as pharmaceuticals, homeopathy, and food supplements. This includes tablets, effervescent granules, powder granules, and (micro)pellets. Maintaining high-quality standards, especially in terms of active ingredient bioavailability, is a constant challenge for the research and manufacturing industries. When choosing a process, several aspects must be considered. Ultimately, the decision will depend on the willingness to invest and the need for efficiency. This article compares different granulation processes and some of their various aspects. The multi-step process, which involves a high-shear granulator and fluidized bed processor, as well as the single-pot process, are safe, efficient, and flexible. If you require a high degree of flexibility and the use of individual processes, choosing a high-shear granulator and fluidized bed processor is a good option, if enough space is available. The single-pot process provides a straightforward and secure solution that is not affected by environmental factors and can be easily applied.

Author Details

Dr. Jessica Kyereme – Flaspöhler- DIOSNA Dierks & Söhne GmbH

Publication Details