Granulation Method Advancements

Granulation Method, During granulation, a critical step in pharmaceutical manufacturing, particles are enlarged using agglomeration techniques. This process is very important in the production of pharmaceutical dosage forms, especially tablets and capsules. By converting fine powders into free-flowing, dust-free granules, granulation allows them to be more easily compressed. However, this presents numerous challenges, mainly due […]

Granulation Method, During granulation, a critical step in pharmaceutical manufacturing, particles are enlarged using agglomeration techniques. This process is very important in the production of pharmaceutical dosage forms, especially tablets and capsules. By converting fine powders into free-flowing, dust-free granules, granulation allows them to be more easily compressed. However, this presents numerous challenges, mainly due to the stringent quality requirements for cast granules, covering aspects such as content uniformity and physicochemical properties such as granule size, bulk density, porosity, hardness, moisture content and shrinkage. Moreover, the physical and chemical stability of the drug makes the granulation process more complex.

There are two main types of granulation processes: wet granulation, which uses liquid, and dry granulation, which occurs without the use of liquid. Choosing an appropriate process requires, among other things, in-depth knowledge of the drug’s physicochemical properties, excipients, and desired flow and release characteristics.

Several technologies play an important role in granulation, including spray drying, roller compaction, high shear mixing, and fluid bed granulation. These techniques have proven effective in overcoming the challenges posed by fragmented processes. However, the field of pharmaceutical granulation technology is dynamic and constantly evolving with the introduction of new and innovative technologies.

This review highlights recent advances in granulation techniques and techniques and covers pneumatic dry granulation, Reverse wet granulation, steam granulation, moisture activated dry granulation, heat bond granulation, freeze granulation and expanded bond foam granulation. Provides insight. Each development is discussed with a brief description that highlights its importance and limitations and provides a comprehensive overview of the current pharmaceutical granulation technology landscape. For example, the advent of steam granulation represents an innovative way to obtain granulated structures by harnessing the power of steam, offering potential advantages in terms of efficiency and product quality. However, issues related to process control and scalability may limit widespread adoption in pharmaceutical manufacturing.

Granulation, a key technology in pharmaceutical manufacturing, involves particle growth through agglomeration and is considered one of the most important steps in the production of pharmaceutical dosage forms, especially tablets and capsules. This process converts small, fine or coarse particles into larger aggregates called granules. The initiation of granulation typically occurs after initial dry mixing of the powder ingredients and active pharmaceutical ingredient (API) to ensure uniform distribution throughout the powder mixture.

In the pharmaceutical industry, granules with a particle size of 0.2 to 4.0 mm are typically used as intermediate products in the 0.2 to 0.5 mm size range. These granules are packaged directly into dosage forms or mixed with other excipients before compressing tablets or filling into capsules. Granule production serves several purposes: B. Improved API uniformity, increased mixture density to improve storage and transportation efficiency, facilitate dosing or dose distribution, and reduce dust during granulation to reduce exposure to toxic substances and risks associated with the process and final product. The overall picture.

Ideal granule characteristics include a spherical shape for improved flowability, a narrow particle size distribution for uniform content and volume dosing, sufficient fineness to fill voids between granules for good compaction and compaction properties, and a fine particle size to prevent breakage and dusting. These include moisture content and sufficient hardness. Receive training in manufacturing.

Granulation is an example of particle design, and the properties of the particles after granulation include particle size of drug and excipients, type, concentration and volume of binder and/or solvent, granulation time and type of granulator, and drying rate (temperature and time). ). Composite particles are formed through processes such as solid bridging, sintering, chemical reaction, crystallization, colloidal particle deposition, adhesion, and cohesion using a high-viscosity binder. Processes involved in particle formation include wetting and nucleation, coalescence or growth, agglomeration, and attrition or cracking.

In tablet compression, a powder mixture containing pharmaceutical excipients and API can be compressed into tablets either directly or using agglomeration or granulation techniques after granulation. Granulation technology can be broadly divided into two types: dry granulation and wet granulation. Dry granulation involves mechanical compaction (screw) or compaction (roller compaction) to bring the dry powder particles together, while wet granulation uses a granulating fluid (binder/solvent) to form a wet mass through the members. Promotes coagulation. Despite the complexity, time and cost associated with multiple process units such as wet massage, drying and sieving, wet granulation remains the most widely used technique in pharmaceutical granulation, requiring a lot of space and multiple equipment.

Process selection for pharmaceutical granulation requires in-depth knowledge of the drug’s physicochemical properties, excipients, and desired flow and release characteristics. Over the years, granulation technologies such as roller compaction, spray drying, supercritical fluids, low/high shear mixing, fluidized bed granulation, extrusion/spheronization, etc. have proven successful in the production of various pharmaceutical dosage forms.

For example, consider roller compaction, a proven technology that compacts dusty materials between two counter-rotating rollers. This process is often used to produce granular pellets because it efficiently produces uniform particle sizes and improves flow characteristics. In real-world scenarios, pharmaceutical companies can use roller compression to improve the structure of tablets to ensure consistent drug release and optimal therapeutic effect.

The pharmaceutical granulation environment is dynamic and subject to continuous development and innovation. Over time, many improvements, modifications, and new techniques and technologies have emerged, reflecting the industry’s efforts to improve the pharmaceutical manufacturing process. These advances contribute to the development of more effective and patient-friendly medicines.

The purpose of this review is to provide readers with information about the latest technologies and techniques related to pharmaceutical granulation. By exploring ongoing developments in granulation technology, the pharmaceutical industry can keep abreast of advancements that can impact the efficiency, quality, and overall success of the drug manufacturing process.


Recent advances in wet granulation

Wet granulation is the most important and most used technology in pharmaceutical production. In this method, a granulating liquid, which may or may not contain a binder, is used to wet mix excipients and an active pharmaceutical ingredient (API) to form granules. Over time, wet granulation has undergone numerous developments, both from a technical and technical perspective, demonstrating its adaptability and versatility in pharmaceutical processes.

An important innovation in wet granulation is the introduction of steam granulation. This technology uses steam as the granulation medium, providing a controlled and efficient granulation medium. Applying steam improves the cohesion of the granules, improving the uniformity and quality of the final product. This innovation solves problems related to moisture content and distribution and contributes to the overall efficiency of the granulation process.

Another important advancement, moisture-activated dry granulation, involves using moisture to accelerate granulation without adding liquid binders. This technology offers the advantage of reducing processing time and energy consumption, making it a more sustainable and cost-effective option. Pharmaceutical manufacturers can leverage these innovations to streamline manufacturing processes and increase overall efficiency.

Heat adhesive granulation is a further development of wet granulation technology. This method produces granulation by promoting adhesion between particles through controlled heating. Precise application of heat ensures optimal binding and cohesion, resulting in granules with the desired properties. These innovations are examples of industry efforts to improve and optimize manufacturing processes for pharmaceutical formulations.

Melt granulation, a state-of-the-art method, uses a molten binder to bind particles into granules. This technology offers advantages in terms of better homogeneity and dissolution properties of the final product. Pharmaceutical formulations developed using melt granulation exhibit improved stability and bioavailability, demonstrating the potential of this approach to revolutionize drug delivery systems.

Freeze granulation is another innovative technology that produces granules by freezing. In this method, ice bridges are formed between particles, resulting in the development of well-defined and uniform particles. The freeze granulation process is particularly convenient for sensitive or heat labile substances and ensures the therapeutic integrity of the active ingredients.

Expanded binder or foam granulation represents a unique innovation in wet granulation in which a blowing agent is introduced to form a foam and then acts as a binder in the granulation process. This technology offers benefits such as improved flow properties and compressibility of the granules and contributes to the overall efficiency of downstream processing and tablet production.

Counter-wet granulation is an advanced variant in which dry powder is added to the wet mass to form granules. This method provides a controlled and efficient way to achieve granulation while minimizing the use of liquid binders. The Reverse wet granulation process provides better control of particle size distribution and better control of powder flow characteristics.

The continuous development of innovative wet granulation technologies such as steam granulation, moisture-activated dry granulation, heat adhesive granulation, melt granulation, freeze granulation, expanded binder or foam granulation and Reverse wet granulation is driving the pharmaceutical industry. is promising. We proceed with the production process. These innovations not only address the challenges of traditional wet granulation, but also provide solutions that improve the efficiency, product quality, and stability of pharmaceutical manufacturing.


  • Freeze granulation
  • Foam granulation
  • Melt granulation
  • Moisture-Activated Dry Granulation (MADG)
  • Reverse wet granulation
  • Steam Granulation
  • Thermal Adhesion Granulation (TAG)
Freeze Granulation

Freeze-drying technology, following cutting-edge spray freezing and freeze-drying methods, is revolutionizing granule production through the seamless integration of liquid nitrogen and advanced drying technology. This innovative process begins by carefully spraying small droplets of a slurry or suspension into liquid nitrogen to quickly condense them into granules. In the subsequent freeze-drying step, in which the frozen droplets are sublimated, spherical and free-flowing particles are formed without separation effects.

To understand the importance of this technology, let us consider its application in the pharmaceutical industry. Protects organic compounds from damage in mild environments through low temperature and freeze-drying, improving stability and solubility. The versatility of freeze-drying extends to a wide range of materials in disperse form, making it suitable for mixing fine powders with appropriate additives. What makes this process special is its unique ability to preserve the structure and homogeneity of the particles in the original slurry or suspension, which provides a major advantage for granulation where precise particle size and homogeneity are required.

Real-world applications demonstrate the wide-ranging benefits of this technology. Redispersible parenteral formulations, nanomaterials, and solid self-emulsifying drug delivery systems benefit greatly from granulation via freezing as they maintain size and homogeneity, which are critical for performance. Companies such as Powderpro AB, a spin-off of the Swedish Ceramic Institute, have been developing, producing and selling freeze granulation equipment using this technology since 2000.

This process is characterized by the following important advantages: B. Because there is no particle movement or molecular bonding, the concentration of particles can be controlled through suspended solids, void-free particles are produced, and high homogeneity is possible. The gentle drying process makes heat-sensitive compounds easier to use and broadens their application range. Additionally, the environmentally friendly use of water as a process medium contributes to sustainability, although it may suffer from the low solubility of some drugs and processing aids.

Freeze granulation technology has proven to be an innovative approach with far-reaching implications, shaping the granule manufacturing landscape across various sectors, especially the pharmaceutical industry. The ability to maintain particle size, homogeneity and structural integrity is an important tool in the arsenal of modern materials processing technologies.

Cold granulation, also known as cold granulation or cold casting, is a unique granulation technology that involves freezing a liquid suspension and then sublimating the freezing solvent to form a porous granule structure. Like any other process, cold granulation has advantages and disadvantages.

Advantages of Freeze Granulation

  • Porous Structure
  • Preservation of particle shape
  • Low shear
  • Particle size distribution control
  • Environmentally friendly
Porous Structure:

One of the main advantages is creating a very porous structure. The freeze-drying process forms a network of interconnected pores within the granules, which can improve properties such as dissolution rate and surface area in pharmaceutical and materials science applications.


Preservation of particle shape:

During freeze granulation, the original particle shape of the granulated material is often maintained. This can be important in applications where maintaining raw material properties is critical to product performance.


Low shear:

This process requires minimal shear force on the particles during granulation, which is beneficial in maintaining fine material properties that can be damaged by traditional granulation methods.


Particle size distribution control:

Granulation via freezing allows for more effective control of particle size distribution, resulting in more uniform granules. This is particularly advantageous for industries where particle size plays an important role in the properties of the final product.


Environmentally friendly:

This process generally uses water as a solvent, and the solvent can be recovered and reused, making freeze granulation relatively environmentally friendly compared to other granulation technologies that may use organic solvents.


Disadvantages of Freeze Granulation

  • Longer processing time
  • Equipment Complexity
  • Scalability Challenge
  • Energy intensive
Longer processing time:

Freeze granulation processes often require longer processing times than traditional granulation methods. Freezing and sublimation steps can increase overall production time and affect efficiency and productivity.


Equipment Complexity:

The equipment required for freeze granulation can be more complex and expensive. Special freezers and control systems are required to ensure a successful granulation process.


Scalability Challenge:

Scaling cryogranulation from laboratory scale to industrial scale can be difficult. As volumes increase, it becomes more difficult to achieve consistent results and maintain control over process variables.


Energy intensive:

This process can be energy intensive, especially during the freezing and sublimation steps. These aspects must be considered both in terms of operating costs and environmental impact.


Foam granulation

Foam granulation, an innovative technology similar to spray agglomeration, has revolutionized the process of incorporating liquid or water-based binders into powder particles. Unlike the traditional method of spraying or pouring a liquid binder onto the powder, foam granulation uses a foam binder. This innovative method was introduced by the Dow Chemical Company in 2003 and involves using a foam generator in a binder solution tank with a high shear or fluidized bed granulator. By introducing the binder into the foam rather than spraying or casting, this technology eliminates problems associated with inconsistent binder distribution that can affect tablet hardness and drug release in high shear and fluid bed wet granulation applications.

The unique advantage lies in the superior surface and volume properties of foamed binders compared to sprayed water. This technology uses these properties to improve binder distribution in the powder particles using lower amounts of binder than traditional spray granulation methods. Traditional spray methods often pose problems such as uneven wetting, excessive wetting, requiring excessive amounts of water and binder, and complex drying processes to remove excess water. In comparison, the expandable binder has high wettability, so the particles are well coated and do not overmoisten. The result is less binder, greater distribution, improved reproducibility and shorter processing times. Eliminating spray nozzles also reduces process fluctuations and clogging problems.

In addition to these advantages, foam granulation has proven to be useful for high potency/low dose drug formulations as it ensures uniform distribution of the drug. Additionally, minimal water consumption and short processing times make it suitable for water-sensitive formulations as well as immediate controlled release formulations. Standard equipment such as high/low shear mixers and fluid bed granulators combined with foam generators facilitate the smooth introduction of this technology.

Despite the numerous advantages, further research is needed to understand aspects such as foam quality, process parameters, device dynamics, flow patterns, and mixing behavior. Overcoming regulatory approval challenges is a significant hurdle and highlights the need for continued research and development in this innovative sector.

Advantages of foam granulation:

  • Improved delivery
  • Improved diffusion/absorption rate
  • Reduce processing time
  • Reduce the amount of binder
  • Spray nozzle troubleshooting
Improved delivery:

Compared to traditional spray granulation methods, foam granulation distributes the binder more uniformly and predictably into the powder particles.
Example: In pharmaceutical manufacturing, uniform tablet hardness and uniform binder distribution are critical to drug release.


Improved diffusion/absorption rate:

Foam binders have a high dispersion-wetting ratio, which is better for particle coating rather than overwetting. This contributes to increased efficiency and a more controlled process.
Example: In pesticide production, precise coating of granules is essential for efficient and targeted application.


Reduce processing time:

Foam granulation typically reduces overall processing time compared to traditional methods, increasing production efficiency.
Example: Rapid processing can be advantageous in industries such as food production, where it can increase overall productivity by reducing the time required for granulation.


Reduce the amount of binder:

This technology ensures effective granulation while using small amounts of binder. This helps you save money and reduce your environmental impact.
Example: The use of low-grade binders may be particularly advantageous for pharmaceutical products where reduced amounts of excipients are required.


Spray nozzle troubleshooting:

Eliminates problems associated with foam granulation spray nozzles such as clogging and processing variability, providing a more reliable and efficient manufacturing process.
Example: Avoiding nozzle problems is important when producing detergents where consistent granule size is critical to product performance.

Disadvantages of foam granules:

  • Device compatibility
  • Limited application
  • Regulatory barriers
  • Research and development requirements
Device compatibility:

Foam granulation adjustments may require modifications to existing equipment or additional components (e.g., foam generators), which may increase initial implementation costs.
Example: In the agricultural sector, adapting existing granulation systems to foam technology may require investment in new machinery.


Limited application:

Foam granulation may not be suitable for all materials or formulations, limiting its application to certain industries or processes.
Example: When producing certain specialty chemicals, traditional granular methods may still be preferred due to specific material properties.

Foam granulation offers many advantages in terms of improved binder distribution, reduced binder volume, and increased efficiency, but also presents challenges such as regulatory barriers, ongoing research requirements, equipment compatibility issues, and limited applicability of certain materials or processes.


Regulatory barriers:

This technology may have difficulty gaining regulatory approval and may require extensive documentation and validation to ensure compliance with industry standards.
Example: In the pharmaceutical industry, all new manufacturing methods must undergo rigorous regulatory review to ensure the safety and effectiveness of the product.


Research and development requirements:

More research is needed to fully understand foam quality, process parameters, and device dynamics. This can cause problems during the initial implementation phase.
Example: In the chemical industry, where new processes are constantly being developed, further research is essential to optimize and validate new production technologies.


Melt Granulation

Melt granulation, also called thermoplastic granulation, is a cutting-edge technology that uses soluble binders to promote fusion of powder particles. These binders have the unique property of melting or softening at relatively low temperatures (usually 50-90°C). The granulation process is a process in which the mixture of drug, binder, and other excipients is heated to dissolve or soften the binder, and then the solidified powder is cooled to solidify the molten binder to complete the granulation process.

For practical applications, consider the pharmaceutical industry, where fusion granulation has proven to be an invaluable tool. For example, in a melting process, a mixture of drug, binder, and other ingredients is heated to a temperature above the melting point of the binder. This process allows the incorporation of low melting point binders into solid particle form, making in situ melt granulation possible. However, the spray-on process involves spraying a molten binder, which may contain active ingredients, onto the heated powder, offering a variety of options for adjusting the properties of the final granules.

An important advantage of cast granules is their environmental friendliness. Unlike traditional wet granulation techniques, the melt granulation process does not require organic or aqueous solvents. This solves environmental problems by eliminating the need to capture and recycle organic solvents. Additionally, the absence of water in the process eliminates the wetting and drying steps, making the overall process less expensive in energy and time.

Melt granulation is a promising alternative for water-sensitive materials as it provides stability to moisture-sensitive drugs while improving the physical properties of the drug substance. However, it is important to recognize the biggest drawback of this process: the high temperatures required during operation. These high temperatures can lead to decomposition and oxidative instability of the components, especially for heat labile drugs.

The choice of binder plays an important role in melt granulation. Choices range from hydrophilic to hydrophobic. The choice of soluble binder with specific hydrophilic or hydrophobic properties becomes an important factor affecting the dissolution behavior of the drug.

When it comes to equipment, high shear mixers and fluidized bed granulators have proven to be key tools to effectively perform melt granulation. Interest in melt granulation has increased significantly in recent years due to its several advantages over conventional wet granulation processes and represents a significant advancement in pharmaceutical manufacturing.

Advantages of Melt Granulation:

  • Controlled release formulations
  • Improved stability
  • Simplified process
  • Shorter processing time
  • Uniform particle size distribution
Controlled release formulations:

Melt granulation is suitable for developing controlled release formulations. Water-soluble binders bind drug particles and enable prolonged, controlled release of the active ingredient.

Improved stability:

The use of water-soluble binders can improve the stability of some active pharmaceutical ingredients (APIs) that may be sensitive to moisture. The absence of water in the granulation process can improve the stability of the final product and extend its shelf life.

Simplified process:

Melt granulation requires fewer processing steps than traditional wet granulation methods, for example no liquid binders are required. This simplification can lead to cost savings and improved production efficiency.


Shorter processing time:

The processing time of melt granulation is generally shorter than that of other granulation technologies. The lack of liquid binder and no drying step makes the overall process faster.

Uniform particle size distribution:

Melt granules often produce granules with uniform particle size distribution, which has a positive impact on subsequent processing steps and the overall quality of the final product.

Disadvantages of enamel granulation

  • Difficulty in scaling up
  • Equipment complexity
  • Heat sensitivity
  • Potential API degradation
  • Solubility limitations
Difficulty in scaling up:

Scaling up the fusion granulation process for large-scale manufacturing can be difficult due to the need for specialized equipment and the potential for increased energy consumption. This may limit the scalability of the technology in certain production environments.


Equipment complexity:

Handling molten granular materials may require special equipment. This may increase capital costs and limit the accessibility of this technology to some manufacturing facilities.


Heat sensitivity:

Molten granules expose the formulation to high temperatures, which may not be suitable for some heat-sensitive drugs or excipients. These limitations may affect the choice of materials for the formulation.


Potential API degradation:

Exposure of active ingredients to high temperatures during granulation poses a risk of decomposition of heat-sensitive drugs, potentially impacting the overall quality of the final product.


Solubility limitations:

Some excipients or active ingredients may have limited solubility in the fusion binder, limiting the range of formulations that can be successfully formulated using fusion granulation.

Melt granulation offers numerous advantages, including process simplification and reduced processing times, but limitations such as potential heat sensitivity and equipment complexity must be carefully considered when selecting a granulation technique to achieve a specific pharmaceutical formulation. This is important. Calculating.


Moisture-Activated Dry Granulation (MADG)

Moisture-activated dry granulation (MADG) technology represents a significant departure from traditional wet granulation methods by using minimal water to trigger binder activation and initiate consolidation. This innovative process consists of two important steps: wet agglomeration of dust particles and subsequent moisture absorption and distribution. For example, consider the use of MADG in the pharmaceutical industry to produce immediate controlled release dosage forms.

In the initial stages of MADG, a small amount of water, typically less than 5% (initial 1-4%), is incorporated into the mixture of drug, binder, and other excipients. This water acts as a granulating fluid, activating the binder and promoting flocculation. Once agglomerated, hygroscopic materials such as microcrystalline cellulose or silica are added to absorb excess moisture. These adsorbents play an important role in redistributing moisture within the powder mixture, resulting in a relatively dry granular mixture. Importantly, this process does not require expensive drying steps and the water consumption is much lower than traditional wet granulation techniques, preventing the formation of larger agglomerates.

During moisture redistribution, some aggregates retain their size, but larger aggregates may break apart, contributing to a more uniform particle size distribution in the 150–500 μm range. Despite the misleading nomenclature, it is important to clarify that MADG is not synonymous with traditional dry granulation techniques, including compression or roll forming. Because MADG uses small amounts of water, the term ‘dry granulation’ was deemed inappropriate and the term ‘wet granulation’ was introduced.

The application of MADG in immediate-release and controlled-release dosage forms has been demonstrated to have many advantages over wet granulation, including larger particle size, improved flow, and improved compressibility. Additionally, MADG has wide applicability, time efficiency, and requires low power consumption. The process involves few process variables and is therefore suitable for continuous processing. However, several limitations exist as MADG is not suitable for high drug loadings and moisture-sensitive or hygroscopic drugs due to associated stability and processing issues.

To expedite the MADG process, a high shear mixer with a nebulizer is recommended as the ideal equipment. These machines should be equipped with efficient impellers, blades and grinders to ensure optimal movement of the mass and correct mixing of the granule mass, contributing to the overall success and efficiency of the technology. The term “MADG (Moisture-Activated Dry Granulation)” was coined by the inventor in 1987 and captures the essence of this innovative pharmaceutical granulation method.

Benefits of Moisture-Activated Dry Granulation (MADG)

  • Energy efficiency
  • Improved drug stability
  • Improved powder flow
  • Reduced water usage
  • Short processing time
Energy efficiency:

MADG often requires lower energy consumption than wet granulation processes, which require significant energy input for drying. Eliminating or reducing drying steps in MADG contributes to energy efficiency and cost savings.


Improved drug stability: Because MADG uses less water, it reduces the risk of chemical degradation or hydrolysis of moisture-sensitive drugs, improving drug stability during the granulation process.

Improved powder flow: Water activation of MADG can improve the flow characteristics of granular powder. This is particularly useful in downstream processes such as tablet compression and ensures a smoother, more uniform powder flow during production.


Reduced water usage:

MADG typically requires less water than traditional wet granulation processes. This reduction in water consumption is beneficial for moisture-sensitive drugs or formulations where excess moisture may cause performance degradation or instability.


Short processing time: MADG has a shorter processing time than wet granulation methods, resulting in higher production efficiency and productivity.

Disadvantages of Moisture-Activated Dry Granulation (MADG)

  • Limited control of granule size
  • Potential for excessive humidity
  • Equipment Sensitivity
  • Scalability challenges
  • Limited applicability
Equipment Sensitivity:

MADG may require special equipment designed to handle moisture activation processes. The sensitivity of equipment to moisture content and different processing conditions can be complex and require precise control and monitoring.


Limited applicability:

MADG may not be suitable for all drug formulations or substances. Some drugs or excipients do not respond well to water activation, which may limit the applicability of MADG in certain pharmaceutical manufacturing processes.


Limited control of granule size:

Accurate control of granule size in MADG can be difficult compared to wet granulation methods. These limitations can affect the uniformity of the final product, especially in formulations where particle size distribution is important.


Potential for excessive humidity:

MADG may be exposed to excessive humidity if moisture content is not carefully controlled. If the humidity is too high, the powder may clump or harden, which will affect the particles and quality of the final product.


Scalability challenges: Scaling up the MADG process from laboratory to industrial scale can present challenges in keeping moisture content, particle size, and other critical parameters constant. Ensuring scalability without compromising product quality can be a complex task.

MADG offers numerous advantages, such as reduced water consumption and increased energy efficiency, but also presents challenges related to granule size control, potential for overheating, device sensitivity, scaling issues, and limited applicability of the specific agents attached. Manufacturers should carefully evaluate product characteristics and expected outcomes before selecting MADG with a granular approach.


Reverse wet granulation

Reverse wet granulation, also called reverse-phase wet granulation, represents a breakthrough in wet granulation technology. In this innovative method, the dry powder formulation is soaked in a binding liquid and then carefully ground to form granules. The process begins with preparing a binding solution to which dry powder excipients are added during mixing in a granulator. Alternatively, a hydrophilic polymer and/or binder can be mixed with the solution to form a drug-polymer/binder suspension that acts as a granulation fluid. A mixture of different dry excipients is then soaked in the drug polymer/binder suspension to form wet granules, which are dried and then milled.

In practice, a specific example of Reverse wet granulation is the production of pharmaceutical tablets. Using this technology, tablets exhibit improved flow and handling characteristics compared to traditional wet granulation processes. In particular, tablets manufactured by the reverse wet granulation method showed more uniform disintegration in the dissolution test than tablets manufactured by the conventional method. Controlled fracture is the key mechanism of granule formation in Reverse wet granulation, providing a unique method to achieve desired granulation characteristics.

The main reason for the development of Reverse wet granulation is its potential to improve the dissolution properties of poorly soluble drugs. This is achieved by evenly distributing a binder that acts as a wetting agent. Additionally, this technology promotes adequate wetting of the drug during granulation, resulting in better dissolution. In this process, the tight bond between the drug and the hydrophilic polymer increases the likelihood of substantial and uniform contact, which helps improve dissolution characteristics.

Compared with traditional wet granulation, Reverse wet granulation has many advantages. Produces small, round granules with excellent flow properties that ensure uniform wetting and erosion. The close connection between drugs and polymers makes this technique particularly suitable for drugs that are poorly soluble in water. B. You can use readily available equipment, such as high-speed mixers, while also enjoying the convenience and appeal of this innovative granulation method.

Despite its advantages, it is important to note that Reverse wet granulation can produce granules with larger average bulk diameters and fewer intragranular voids than conventional wet granulation, especially at low binder concentrations. These subtleties highlight the need to carefully consider formulation parameters to optimize the process based on specific drug properties and desired outcomes.


Advantages of Reverse wet granulation

  • Advanced Ingredient Blending
  • Controlled particle size distribution
  • Minimized exposure to heat and moisture
  • Reduced processing time
Advanced Ingredient Blending:

It involves carefully mixing the active ingredients, excipients and binders and mixing dry powders with liquid binders for uniform distribution. This can improve content consistency in the final product.

Controlled particle size distribution: Counter-wet granulation allows precise control of particle size distribution. This is very important in pharmaceutical manufacturing as particle size can affect the properties of the final product.

Minimized exposure to heat and moisture: Unlike traditional wet granulation methods, Reverse wet granulation minimizes exposure to heat and moisture during the initial mixing stage. This can be useful for heat- or moisture-sensitive active pharmaceutical ingredients (APIs) that may degrade under conventional wet granulation conditions.


Reduced processing time:

This process typically involves fewer steps than traditional wet granulation, resulting in shorter processing times and potentially increased production efficiency.

Disadvantages of Reverse wet granulation

  • Application limitations for certain formulations
  • Binder Distribution Issues
  • Potential for dust generation
  • Sensitivity of equipment
  • Susceptibility to separation
Binder Distribution Issues:

Achieving uniform binder distribution in powder mixtures can be difficult, especially for cohesive or low flow powders. Improper binder distribution can cause uneven grain, affecting the quality of the final product.

Application limitations for certain formulations: Rewetting granules may not be suitable for all types of formulations. Some formulations may benefit more from traditional wet granulation methods or other granulation techniques due to the specific properties of the ingredients used.


Potential for dust generation:

Dust can be generated during the first dry mixing step of Reverse wet granulation, which can cause problems in terms of handling, control and potential operator exposure. Dust-related issues can also affect the overall cleanliness of the production environment.


Sensitivity of equipment:

Processes can be sensitive to the type of equipment used, so selecting the right equipment is important. Special equipment may be required to achieve the desired granule properties, which may increase initial installation costs.


Susceptibility to separation:

Some powder mixtures may separate during the mixing and granulation steps, causing fluctuations in granule formation. Minimizing the risk of separation requires careful formulation and process optimization.


Reverse wet granulation offers advantages such as controlled particle size distribution and minimal exposure to heat and moisture, but also presents challenges related to dust formation, equipment sensitivity, binder distribution, separation, and limited application of certain formulations. The suitability of Reverse wet granulation depends on the specific requirements and characteristics of the process.


Steam granulation

The innovative example of steam granulation, a sophisticated wet granulation technology, departs from the traditional practice of using liquid water as a binder. Instead, the state-of-the-art method uses water vapor as a binder, offering numerous advantages that redefine the granulation process.

In its basic state, vapor represents a transparent gas capable of dispersing dust at high speeds. These unique properties create conditions for an innovative granulation experience together with a more favorable heat balance in the subsequent drying steps. During condensation, the vapor forms a thin, hot film on the dust particles that requires minimal additional energy to remove and evaporates smoothly.

A significant advantage of this innovative technology is the improved ability of vapors to disperse and diffuse evenly through dust particles. The result is spherical particles with a larger surface area, a property that not only increases the dissolution rate but also contributes to the overall efficiency of the process. In particular, this method implements ecological principles by eliminating the need for organic solvents and adapting to sustainable practices.

Implementing this technology in practice requires devices such as high-shear mixers connected to steam generators, highlighting the simplicity and feasibility of integration into existing pharmaceutical or manufacturing facilities. However, it is important to recognize that the energy-intensive nature of steam generation is demanding and requires significant energy input.

Additionally, it is important to note that while steam granulation represents a paradigm shift from wet granulation, it is not a one-size-fits-all solution. This technique is sensitive to thermolabile drugs and may not be universally compatible with all binders. These brief considerations highlight the need for a sophisticated approach to select an appropriate granulation method based on the specific properties of the materials involved.

Using steam as a binder in granulation offers several advantages, including better dispersion, formation of spherical granules, reduced processing time, and respect for the environment. However, the energy requirements and selectivity of this method highlight the importance of tailored applications and careful consideration of compatibility with a variety of materials in pharmaceutical and manufacturing environments.


Thermal Adhesion Granulation (TAG)

Wei-Ming Pharmaceutical Company, based in Taipei, Taiwan, has developed an innovative technology called heat bond granulation. This process, similar to wet granulation, is revolutionizing the pharmaceutical industry by using a unique combination of granulating fluids and heat for coagulation.

Unlike moisture-activated dry granulation, which uses only water as the granulation fluid, Wei-Ming technology introduces both water and solvent into the process. Thermal integration plays an important role in promoting the coalescence of dust particles. The mixture of drug and excipients is heated in a closed system in a controlled manner using tumbling rotation while maintaining a temperature range of 30–130°C.

One of the main advantages of this technology is that it does not require a drying process. Efficiency is ensured by adding a minimum amount of granulating liquid, most of which is absorbed into the powder particles during coagulation. After heating, cooling and sieving, granules of the desired particle size can be obtained.

The simplicity and convenience of this method is surprising, especially due to the low moisture and binder content. Because it operates in a closed system, it is very effective in producing highly compressible ingredients or modifying unwanted properties of excipients.

A practical example is the development of new pharmaceutical formulations using heat-adhesive granulation by Wei-Ming. This process produces granules with good particle size, excellent flow properties and high tensile strength. These properties allow direct compression into tablets and ensure that the final product has the required hardness and low brittleness.

However, it is important to recognize the limitations of this technology. Challenges include significant energy consumption and the need for special equipment to generate and control heat. Additionally, this technique is not universally applicable to all binders and is sensitive to heat-labile drugs.

Wei-Ming Pharmaceutical Company’s heat-bonded granulation technology represents a breakthrough in pharmaceutical manufacturing. Although this innovative approach offers numerous benefits, including efficiency, simplicity, and improved product properties, it is important for researchers and manufacturers to consider the limitations associated with it.

Thermal Adhesion Granulation (TAG) is a process used in pharmaceutical manufacturing that uses heat to form adhesive bonds between powder particles, causing granulation. Like any other technology, TAG has its advantages and disadvantages.


Advantages of Thermal Adhesion Granulation (TAG)

  • Continuous processing potential
  • Improved flow characteristics
  • Reduced use of excipients
  • Simplified Process
Continuous processing potential:

TAG can be applied in continuous manufacturing processes to improve the scalability and efficiency of pharmaceutical manufacturing.


Improved flow characteristics:

TAG can help improve the flow characteristics of granules, making downstream processes such as tablet compression more efficient. Granules produced from TAG tend to have good compressibility and good flow properties.


Reduced use of excipients:

Because TAG relies on heat for granulation, it may require fewer excipients or binders than other granulation methods. This may be advantageous for formulations where it is desirable to minimize the use of additional ingredients.


Simplified Process:

TAG simplifies the granulation process by often eliminating the need for traditional binders and liquid solutions. This reduces the number of processing steps, making the method simpler and more efficient.

Disadvantages of Thermal Adhesion Granulation (TAG):

  • Changes in particle size
  • Equipment Complexity
  • Energy consumption
  • Limited applicability
  • Temperature sensitivity
Changes in particle size:

Achieving a uniform particle size distribution may be difficult with TAG as particle size may change when heated. This may affect the overall quality and performance of the final formulation.

Energy consumption: The use of heat in TAG requires energy input and the process can be more energy intensive than some alternative granulation methods. These aspects must be considered in terms of economic and environmental sustainability.


Equipment Complexity:

Implementing TAG may require specialized equipment to precisely control and apply heat. The initial investment and maintenance requirements for such equipment can increase production costs.


Limited applicability:

TAG may not be suitable for all drug formulations or products. The effect may depend on the specific properties of the active pharmaceutical ingredient (API) and excipients used in the formulation.


Temperature sensitivity:

TAG requires the application of heat, which can be detrimental to heat-sensitive materials or formulations. Some drugs or excipients may decompose or cause unwanted reactions at high temperatures.


TAG offers several advantages:

B. Simplifies the granulation process and potentially reduces the need for excipients; however, it has limitations related to temperature sensitivity, particle size control, equipment complexity, and energy consumption. The choice of granulation method depends on the specific requirements and characteristics of the pharmaceutical formulation.



Recent advances in dry granulation

Dry granulation, an essential method in pharmaceutical manufacturing, can be performed in two main ways: roller compaction or slugging. Wet granulation has historically surpassed dry granulation in terms of technological advancement and advancement, but significant progress has been made with the pneumatic dry granulation technology developed by Atacama Labs.

Pneumatic Dry Granulation (PDG) features an innovative technology that seamlessly combines roller compaction and a proprietary air fractionation system to produce granules featuring an exceptional combination of flowability and compressibility. In this innovative process, light compression forces are first applied by compression rollers to produce a compact mass consisting of a mixture of fine particles and granules. The fractionation chamber then uses a pneumatic system to separate fine and small particles from particles of the desired size.

Once particles of the desired size pass through a fractionation chamber and are compressed into tablets, the accompanying fine and small particles are sent to a cyclone-like device. This is where you come across an important decision point. Immediate reprocessing through recycling or reprocessing in roller compactors or storage in the desired granular form for subsequent reprocessing.

The versatility of PDG technology is evident as it has proven adept at producing well-flowing granules for a variety of formulations to produce compact products with tensile strengths of approximately 0.5 MPa. Additionally, compared to conventional roller compaction processes, this technology offers the advantage of high active material loadings of around 70 to 100%, as noticeable smoothness can be achieved even at low roller compaction forces (low solids content).

In addition to the benefits of smoothness, PDG technology offers many additional benefits, including accelerated processing speeds, cost-effectiveness, minimal material waste, and reduced dust due to the drive’s closed design. However, despite these advantages, several challenges remain, such as the impact of recycling on granule quality, compatibility with low-volume formulations, and fragility issues.

Pneumatic dry granulation technology not only represents a significant advance in dry granulation engineering, but also an innovative solution that has the potential to transform pharmaceutical manufacturing processes with the potential to deliver higher efficiency, lower costs and better product quality. represents .

Aerodynamic dry granulation is a pharmaceutical manufacturing process that forms granules without the use of liquid binders. A roller compactor is used to apply compressive force to the dry powder particles and then reduce them to pulverized size. Like any other technology, pneumatic dry granulation has advantages and disadvantages.

  • Advantage
  • Binder-free process
  • Cost savings
  • Faster processing
  • Uniform granule size
Binder-free process:

Pneumatic dry granulation does not require liquid binders, making it suitable for moisture-sensitive materials. The result is a final product with increased stability and durability.

Cost savings: By eliminating the purchase, storage and disposal of liquid binders, pneumatic dry granules can reduce costs on raw materials and related processing steps.


Faster processing:

This process is generally faster than wet granulation methods because it does not require the drying time associated with liquid binders. This can help increase productivity and efficiency in pharmaceutical manufacturing.


Uniform granule size:

Aerodynamically, dry granulation can produce granules with uniform size and distribution. This uniformity is important to ensure consistent drug content and potency in the final dosage form.


  • Dust generation
  • Equipment Complexity
  • Energy consumption
  • Limited powder flow characteristics
  • Tablet hardness issues
Dust generation:

Fine dust particles or dust may be generated due to drying of the process. Dust control is essential to maintain a safe working environment and prevent cross-contamination between batches.


Equipment Complexity:

Pneumatic dry granulation usually requires the use of special equipment such as roller compactors and mills. The initial investment and maintenance costs of these devices can be expensive.

Energy consumption: Roller compaction requires energy to utilize the compaction force and the overall energy consumption of the process must be considered. However, the goal of technological advancements is to optimize the energy efficiency of pneumatic dry granulation systems.


Limited powder flow characteristics:

The properties of the powder material can affect the success of dry pneumatic granulation. Materials with poor flow characteristics may not compress efficiently and may have difficulty achieving the desired particle size.


Tablet hardness issues:

It can be difficult to achieve the desired tablet hardness without using liquid binders. Additional steps or process changes may be required to ensure that the tablets have the required mechanical strength.

Dry pneumatic granulation offers many advantages, especially in terms of binder absence, speed and uniformity. However, challenges such as dust generation and tablet hardness must be carefully addressed and methods selected based on the specific properties of the material to be processed and the desired properties of the final product.


Choosing a Wet Granulation Method

The choice of wet granulation method depends on the specific characteristics of the product to be manufactured, the desired characteristics of the final granulation, and the efficiency and cost-effectiveness of the process. We briefly discuss each approach and provide examples where appropriate.


  • Freeze granulation
  • Foam Granules
  • Melt granulation
  • Moisture-activated dry granulation (MADG)
  • Reverse-wet granulation
  • Steam granulation
  • Thermal Adhesion Granulation (TAG)
Freeze Granulation:

The process involves precipitating a liquid binder into a powder mixture.
Example: In the ceramics industry, freeze-drying can be used to produce granules for the production of high-performance ceramics with improved sintering properties.

Foam Granulation:

Liquid or water-based binders are added into the foam to improve binder distribution.
Example: In the pharmaceutical industry, foam granulation can be useful to produce tablets with consistent drug release profiles and better reproducibility.


Melt Granulation:

Granulation occurs by dissolving the binder, which solidifies upon cooling.
Example: The plastics industry can use melt granulation to produce polymer granules of controlled size and shape.

Moisture-activated dry granulation (MADG):

This method involves dry granulation followed by water activation for agglomeration.

Example: In detergent production, moisture-activated dry granulation can produce free-flowing granules that are easy to handle and package.


Reverse-wet granulation:

In this method, the powder is wetted with a liquid binder after the dry mixing step is initiated.

Example: Pharmaceutical tablet formulations where the active pharmaceutical ingredient (API) is sensitive to moisture and binders must be added carefully after initial mixing.


Steam granulation:

The use of steam conditions causes dust particles to coagulate.
Example: Steam granulation can be used in the fertilizer industry to produce granules with improved flow characteristics and reduced dust.


Thermal adhesion Granulation (TAG):

With TAG, heat is applied to create the adhesion needed to form granules.
Example: TAG can be used in the food industry to granulate ingredients in the production of grain products to improve texture and flavor.

The choice of the most appropriate method depends on factors such as product type, required granularity, sensitivity of the material, and overall efficiency of the production process. For example, in the pharmaceutical industry, foam granulation may be preferred for drugs that are more sensitive to wetting, while steam granulation may be applied in fertilizer production to improve the fluidity of granules. It is important to carefully consider the specific requirements of each product and the benefits offered by each granulation method.

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