Granulation methods pdf

Try out PMC Labs and tell us what you think. Learn More. Granulation, the process of particle enlargement by agglomeration technique, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules. Granulation process transforms fine powders into free-flowing, dust-free granules that are easy to compress.

Nevertheless, granulation poses numerous challenges due to high quality requirement of the formed granules in terms of content uniformity and physicochemical properties such as granule size, bulk density, porosity, hardness, moisture, compressibility, etc.

Granulation process can be divided into two types: wet granulation that utilize a liquid in the process and dry granulation that requires no liquid.

The type of process selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, to name a few. Among currently available technologies, spray drying, roller compaction, high shear mixing, and fluid bed granulation are worth of note. Like any other scientific field, pharmaceutical granulation technology also continues to change, and arrival of novel and innovative technologies are inevitable. This review focuses on the recent progress in the granulation techniques and technologies such as pneumatic dry granulation, reverse wet granulation, steam granulation, moisture-activated dry granulation, thermal adhesion granulation, freeze granulation, and foamed binder or foam granulation.

This review gives an overview of these with a short description about each development along with its significance and limitations. Granulation, a technique of particle enlargement by agglomeration, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules.

Generally, granulation commences after initial dry mixing of the necessary powder ingredients along with the active pharmaceutical ingredient API , so that a uniform distribution of each ingredient throughout the powder mixture is achieved.

Although granules used in the pharmaceutical industry have particle size in the range of 0. Granules are produced to enhance the uniformity of the API in the final product, to increase the density of the blend so that it occupies less volume per unit weight for better storage and shipment, to facilitate metering or volumetric dispensing, to reduce dust during granulation process to reduce toxic exposure and process-related hazards, and to improve the appearance of the product.

The primary methods by which the agglomerated granules are formed include solid bridges, sintering, chemical reaction, crystallization and deposition of colloidal particles. The series of mechanisms by which granules are formed from the powder particles encompass wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage.

Blend of powders containing pharmaceutical excipients and API can be compressed into tablets either by direct compression or after making granules by agglomeration or granulation techniques Fig.

The granulation technique may be widely categorized in to two types, dry granulation and wet granulation, based on the type of method used to facilitate the agglomeration of powder particles Fig. Among these two techniques, wet granulation is the most widespread granulation technique used despite the fact that it involves multiple unit processes such as wet massing, drying and screening, which are complex, time consuming, and expensive requiring large space and multiple equipment.

The type of process selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, etc. Pharmaceutical granulation technology continues to change, and various improved, modified, and novel techniques and technologies have been made available along the course.

The aim of this review is to give the reader a glimpse of the latest techniques and technologies with regard to pharmaceutical granulation. Subsequently, this review gives a short description about each development along with its significance and limitations, which are summarized in Table 1. Dry granulation could be achieved either by roller compaction or by slugging. The two different types are illustrated in the schematic diagram Fig.

There has not been much progress in the dry granulation technique and technology in comparison to wet granulation, except for one important innovation known as pneumatic dry granulation technology developed by Atacama LabsOy Helsinki, Finland , which is described below.

Schematic diagram of dry granulation and two different techniques. Method I is roller compaction and Method II is slugging.

Pneumatic dry granulation PDG , an innovative dry granulation technology, utilizes roller compaction together with a proprietary air classification method to produce granules with extraordinary combination of flowability and compressibility. However, the influence of recycling on the granule quality, suitability with low dose formulations, friability, etc.

The description of its significance and limitations are summarized in Table 1. Wet granulation is the widely used technique and the granules are produced by wet massing of the excipients and API with granulation liquid with or without binder. The steps involved in conventional wet granulation technique could be seen in Fig.

Wet granulation has witnessed various technical and technological innovations such as steam granulation, moisture-activated dry granulation or moist granulation, thermal adhesion granulation, melt granulation, freeze granulation, foamed binder or foam granulation, and reverse wet granulation. The significance and limitations of the recent wet granulation techniques and technologies are summarized in Table 1. Reverse wet granulation or reverse-phase wet granulation is a new development in the wet granulation technique that involves the immersion of the dry powder formulation into the binder liquid followed by controlled breakage to form granules.

The resulted wet granules were milled after drying. The granules produced by this process were found to have good flow and handling characteristics like those produced with wet granulation process. In addition, tablets formed from these granules eroded more uniformly during dissolution testing as compared to usual wet granulation technique. The schematic diagram of this process is presented in Fig.

Controlled breakage was proposed to be the predominant granule formation mechanisms in reverse wet granulation technique. It also increases the chances of adequate and uniform contact between the drug and hydrophilic polymer for better dissolution. These improved granule characteristics result in even erosion of tablets during dissolution. The advantages of this technique over conventional wet granulation include small and spherical-shaped granules with improved flow properties, uniform wetting and erosion of the granules.

This technique could be suitable for poorly water-soluble drugs because of the intimate association between a drug and the polymer. Usability of currently available equipment such as high speed mixer is another merit of this technique. However, this technique produced granules with a greater mass mean diameter and lower intragranular porosity when compared to the conventional wet granulation at lower binder concentrations. In steam granulation as a new wet granulation technique, water steam is used as binder instead of traditional liquid water as granulation liquid.

Steam, at its pure form is transparent gas, and provides a higher diffusion rate into the powder and a more favorable thermal balance during the drying step. After condensation of the steam, water forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its elimination, and evaporates more easily.

The advantages of this process include the higher ability of the steam to distribute uniformly and diffuse into the powder particles, production of spherical granules with larger surface area, and shorter processing time ecofriendly no involvement of organic solvents.

An equipment such as high-shear mixer coupled with a steam generator would be enough for this technique. However, this method requires high energy inputs for steam generation.

Besides, this process is not suitable for all binders and is sensitive to thermolabile drugs. The granules produced by this process have higher dissolution rate due to increased surface area of the granules compared to conventional wet granulation process. This technique is a variation of conventional wet granulation technique.

It uses very little water to activate a binder and initiate agglomeration. Agglomeration takes place when the granulating fluid water activates the binder.

Once the agglomeration is achieved, moisture-absorbing material such as microcrystalline cellulose, silicon dioxide, etc. The moisture absorbents absorb the moisture from the agglomerates, resulting in moisture redistribution within the powder mixture, leading to relatively dry granule mixture. During this moisture redistribution process, some of the agglomerates remain intact in size without change, while some larger agglomerates may break leading to more uniform particle size distribution.

It does not require an expensive drying step. The process does not lead to larger lumps formation since the amount of water used is very small compared to usual wet granulation. Some authors believe that dry granulation involves the use of a roller compaction or a slugging step followed by milling to obtain granules. The application of MADG to an immediate-release and controlled-release dosage forms showed the advantages of wet granulation such as increased particle size, better flow and compressibility.

However, this technique could not be used for the preparation of granules that require high drug load and for moisture sensitive drugs and hygroscopic drugs due to stability and processing problems associated with these types of drugs. A high-shear mixer coupled with a sprayer would be a suitable equipment for the MADG process. An ideal machine should be equipped with efficient impellers, blades, and choppers to allow good mass movement and proper mixing of the granulation mass.

Wei-Ming Pharmaceutical Company Taipei, Taiwan has developed this technique, and the thermal adhesion granulation, analogous to moist granulation, utilizes addition of a small amount of granulation liquid and heat for agglomeration. Unlike moisture activated dry granulation which uses water alone as granulation liquid, this process uses both water and solvent as granulation liquid.

In addition to this, heat is used to facilitate the granulation process. This technique eliminates the drying process due to the addition of low amount of granulation liquid, which is mostly consumed by the powder particles during agglomeration.

Granules of the required particle size can be obtained after cooling and sieving. This technique is quite simple and convenient with low moisture and binder contents in a closed system for preparing highly compressible materials or for modifying the poor characteristics of excipients. Besides, this technique provides granules with better particle size, good flow properties and high tensile strength that could be directly compressed into tablets with adequate hardness and low friability.

The limitations of this technique are requirement of considerably high energy inputs and special equipment for heat generation and regulation. This technique is not suitable for all binders and is sensitive to thermolabile drugs. Cooling of the agglomerated powder and the consequent solidification of the molten or soften binder complete the granulation process. More specifically, the melt-in procedure of melt granulation process includes heating a mixture of drug, binder and other excipients to a temperature within or above the melting range of the binder.

On the contrary, the spray-on procedure encompasses spraying of a molten binder, optionally containing the drug, onto the heated powders. Melt granulation is an appropriate alternative to other wet granulation techniques which are used for water sensitive materials. Melt granulation method could be efficiently applied in order to enhance the stability of moisture sensitive drug and further to improve the poor physical properties of the drug substance.

The binders used for this process could be either hydrophilic or hydrophobic. The equipments that could be used for melt granulation are high-shear mixer and fluidized bed granulator.

Freeze granulation technology, spray freezing and subsequent freeze drying, involves spraying droplets of a liquid slurry or suspension into liquid nitrogen followed by freeze-drying of the frozen droplets. The above-mentioned steps are depicted as schematic diagram in Fig. This process yields spherical free-flowing granules that could be formed by using both water based and solvent based slurries. The significance of this technology is that the structure and homogeneity of the particles in the slurry or suspension are retained in the granules.

Although various kinds of material in dispersed form can be granulated using this technology, it is suitable for the preparation of fine powder mixes with proper additives for subsequent processing. This technology could be useful for the preparation of granules that needs to be prepared from suspensions whose particle size and homogeneity need to be preserved. Eventually, re-dispersible parenteral formulations, nanomaterials, solid self-emulsifying drug delivery systems, etc.

The suspension quality always determines and reflects the granule quality in terms of homogeneity. According to PowderPro AB, compared with spray drying, freeze granulation obviously produces protein particles with light and porous characteristics, and making powders with superior aerosol performance due to favorable aerodynamic properties. Originally, this process was developed by Swedish Ceramic Institute in the late This foam binder technology was first introduced by Dow Chemical Company Midland, MI in for delivering aqueous binder systems in high shear and fluid bed wet granulation applications.

Adding the binder solution as foam rather than a spray eliminates the problems of inconsistent and unpredictable binder distribution that can affect tablet hardness and drug release. This technology exploits the characteristics of the foamed binder to successfully improve the distribution of binder onto the powder particles, even at a binder amount lower than that required in the conventional spray granulation method.

Besides, the sprayed liquid droplets have a low spread-to-soak ratio, which means they tend to soak into powders and cause overwetting rather than spreading on the surface of the particles, requiring high levels of water and binder, and eventually drying to remove excess water. On the contrary, foamed binders have a high spread-to-soak ratio, and because of this the binders are coated onto the particles rather than soaked, leading to less amount of binder and more consistent binder distribution.

These factors improve the reproducibility and shorten the processing time. Most importantly, this technology eliminates the spray nozzles and its related processing variables and clogging problems.

Due to the involvement of low amount of water and short process time, water sensitive formulations could also be prepared using this technology in addition to immediate release and controlled release formulations.

Although this technology merits in myriad ways, further understanding of foam quality, process parameters, equipment, flow patterns, mixing behavior, etc.

Besides, the regulatory approval would be a huge hurdle that needs to be overcome. Technical and technological innovations that improve and ease existing processes could contribute to improved processability and quality of the product formulations in addition to a substantial impact on the product development, time and economy. Obviously, the pharmaceutical granulation techniques and technologies have improved over the years. Nevertheless, efficient and cost-effective manufacturing methods have always been the keen interest of the pharmaceutical industries, which catapults the research and development of new and improved technologies by the interdisciplinary scientists of pharmaceutical companies globally.

During the formulation development, each drug substance poses a unique challenge that must be taken into consideration at the process selection stage by the formulation development scientists. Each technique has its own merits and limitations, and the type of technique and technology selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, etc.

The accuracy or condition of slug is not too important. Only sufficient pressure to compact the powder into uniform slugs should be used. Once slugs are produced they are reduced to appropriate granule size for final compression by screening and milling. In a roller compactor material particles are consolidated and densified by passing the material between two high-pressure rollers.

The densified material from a roller compactor is then reduced to a uniform granule size by milling. Roller compaction dry granulation process is capable of handling a large amount of material in a short period of time. As a special subtype briquetting utilizes special designed compaction rolls which divides the compacted powder in pieces briquettes.

For dry granulation the compaction force in extend and uniformity of distribution is essential in regard to uniformity of granules porosity to ensure uniform hardness and disintegration of the final product.

These parameters need to be optimized depending on the materials and the type of equipment used in order to obtain products of desirable quality. The pneumatic dry granulation process is a new and patent pending technology. The granulation process is based on the use of roller compaction with very low compaction force together with a proprietary air classification method. The method enables production of granules with extraordinary combination of flow ability and compressibility.

The granules produced by Pneumatic Dry Granulation and tablets produced show fast disintegration properties, offering the potential for fast release dosage forms, and Release time can be tailored to requirements.

PDG technology can achieve, high drug loading, even with difficult APIs and combinations along with Taste masking and Excellent stability. You must be logged in to post a comment.

Long processing time, a relatively high capital investment on heavy duty presses or compactors. Steps involved in dry granulation process I. Tablet compression In dry granulation method the primary powder particles are aggregated at high pressure. The two different types are illustrated in below: Slugging process how well a material may slug will depend on the below terms Compressibility or cohesiveness of the matter, Compression ratio of powder Density of the powder Machine type Punch and die size Slug thickness Speed of compression Pressure used to produce slug Granulation by slugging is the process of compressing dry powder of tablet formulation with tablet press having die cavity large enough in diameter to fill quickly.

Disadvantages of Slugging: single batch processing frequent maintenance changeover poor process control poor economies of scale low manufacturing output per hour excessive air and sound pollution, Increased use of storage containers, more energy and time required to produce Roller compaction: In a roller compactor material particles are consolidated and densified by passing the material between two high-pressure rollers.

Pneumatic Dry Granulation: The pneumatic dry granulation process is a new and patent pending technology. Solanki, Tarashankar Basuri, Jalaram H.