Granulation Method and Process Monitoring Matter

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The characteristics of tableted solid dosage drugs often depend on the granulation process, so selecting the most appropriate granulation technique and monitoring the process are crucial

Granulation is a key processing step in the production of many solid dosage drugs. It is often necessary to convert powdered drug formulations into a physical form that has improved flow and compaction characteristics to produce tablets with uniform content and consistent hardness and other properties. During granulation, powder particles adhere to one another to form agglomerates, and the size of the particles is increased. There are several methods that can be used for the granulation of active pharmaceutical ingredients (APIs) and partial or complete solid dosage formulations. The most widely used techniques include wet and dry granulation. There are numerous other approaches, however, that are used less frequently, such as melt granulation, fluid-bed granulation, spray-drying granulation, extrusion granulation, rotary granulation, slugging, foam granulation, and moisture-activated granulation. (Direct compression is not discussed here as it does not require a separate granulation step.) Selection of the most appropriate granulation process is important because the consequences can be significant with respect to the performance of the tablet.

Choice of methods
Wet granulation is the oldest and most common granulation technique and can be accomplished using different types of equipment, including high-shear, fluid-bed, and twin-screw granulators. It involves blending at high and/or low shear forces with the addition of a liquid. In fluid-bed granulation, for example, an atomized liquid is sprayed from the top or bottom directly onto the solids under a continuous air stream with little or no shear,

“While wet granulation is used for a large number of pharmaceutical drugs, it does have the drawback of being a high-energy process, because drying is necessary once the wet granulation process is complete,” notes Dejan Djuric, manager of scientific operations at LB Bohle. The energy consumption can be slightly reduced using spray-dry granulation, in which a liquid containing dissolved or suspended solids is atomized and rapidly dried using a controlled air stream to produce a dry powder, which is agglomerated by forcing it again into the atomizing zone, according to Shaukat Ali, technical sales manager with BASF. Djuric adds that twin-screw granulation has the greatest potential of the wet-granulation methods because it is a robust, continuous process.

Dry granulation via roller compaction is, on the other hand, the granulation method of choice with respect to cost. It involves the direct physical compaction of the dry powder, resulting in densification or agglomeration. Dry granulation is also attractive because it can be applied in continuous granulation processes and is suitable for APIs that are moisture and/or temperature-sensitive.


Each of the more specialized granulation processes has special features that make them suitable for powdered APIs/formulations with specific physical characteristics or that need to be converted into granules with specific properties. For instance, in melt (or thermoplastic) granulation, a thermoplastic or low melting binder is melted and mixed with the dry powder at higher temperatures, and then the mixture is quenched by cooling, which allows the binder to hold the granules together via solid bridges, according to Ali. With extrusion/spheronization granulation, a pressure gradient force is used to wet or plasticize the mass through an orifice with a linear shear while in rotary granulation, a central rotating disk, rotating walls, or both create centrifugal or rotational forces that spheronize, agglomerate, and/or densify a wetted or non-wetted dry powder. Finally, in slugging, the formulation blend is slugged at a relatively lower compression force, and the resulting granules from the slugs are further compressed into the desired dosage while foam or moisture-activated granulation involves continuous exposure of the powder to a foam (moisture) generated by bubbling of air through a binder solution, thus, allowing the granulation to take place under nearly dry conditions.

Consideration of API characteristics critical
While often the granulation method is determined based on what techniques are readily available, the characteristics of the API, such as the melting point (for processing temperature), toxicity (containment issues), particle form and size (flowability), moisture/temperature sensitivity, compressibility/compactability (needed amount of shear), must be considered. In addition, production aspects, such as throughput, scale-up ability, and production time, must also be considered, according to Djuric. “Most importantly, an inappropriate choice of granulation method can lead to API destruction, an improper drug-release profile, compression problems, and more,” he adds. Thus, the characteristics of the final tablets depend on the granulation process, and it is important to identify the appropriate granulation technique for each drug formulation.

APIs that are good to sparingly soluble in water and amorphous can be granulated with either wet or dry methods. For APIs with poor flowability and compressibility, fluid-bed granulation remains a viable choice, while APIs that are sensitive to moisture but stable at higher temperatures can be granulated using melt granulation. For insoluble and highly crystalline drugs with poor solubility, melt granulation and/or spray-drying granulation may be preferred. Slugging is an option for APIs with poor flowability that are also highly sensitive to hydrolysis, but Ali notes that fluctuations in the forces applied to the individual slugs can lead to variability in the particle size of the granules and, hence, result in reduced content uniformity. In such cases, roller compaction is a preferable choice.  Finally for APIs that will be formulated into tablets with taste masking and/or controlled release profiles, fluid-bed granulation is widely used because it enables the formation of coating layers.

More than 70% of tablets are designed and developed using wet-granulation processes, according to Ali, in part due to the availability of a wide selection of desired fillers, binders, and disintegrants for these methods. He further points out that wet granulation is often used in the development of very low dose drugs that are challenging to consistently formulate as tablets with good content uniformity.

Monitoring solutions
As with any type of formulation, the goal is to obtain the desired drug product with the fewest necessary processing steps and the lowest cost. For solid dosage drugs, that means using the granulation (if required) that provides a tablet with the desired properties (appearance, uniformity, drug-release profile) using the least number/amount of excipients possible and as rapidly as possible. Djuric adds that it is necessary to carry out small-scale experiments to confirm that the chosen method works for the specific formulation because computational tools, while helpful, are not sophisticated enough to be relied upon completely. “The recent introduction of small-scale equipment that accurately predicts granulation behavior for commercial-scale runs has been very advantageous for the more rapid development of granulation processes,” he says.

Identifying any special techniques or methods to ensure a robust granulation method for tableting is often challenging, according to Ali. “Successful granulation depends on the excipients and the API (or APIs), their compatibility in the formulation blend, and the granulation technique used,” he explains. In wet granulation, for instance, the physical characteristics of the powder mixture change with time as agglomeration and densification proceed. The characteristics of the formed granules also depend on the processing parameters, such as the amount and viscosity of granulating fluid, the rate of granulation, and the impeller speed, which must be determined for each granulation process in order to obtain a robust tablet with good quality and performance. 

Beyond these issues, it is important to determine the “end point” of a granulation process in order to obtain granules with the desired particle size and porosity, and with good flowability and compressibility, according to Ali. “Finding an adequate and precise method for determination of the right end point, which is critical for granulation in scale-up and production batches, is highly warranted due to the current lack of accurate and reproducible methods,” he observes.

Need for innovative technologies
As granulation becomes more prevalent in the industry, the need for innovative technologies for monitoring the granulation process is also growing.  New on-line monitoring spectroscopic/microscopic methods, such as near infrared (NIR), acoustic emission, focused beam reflectance measurement (FBRM), and particle video measurement (PVM), for the determination of the end point of granulation are meeting some of these needs, according to Ali. With NIR, the frequencies of certain functional groups and their interactions in the granules during processing can be determined while acoustic emission detects sounds that are analyzed using high-frequency piezoelectric sensors. FBRM uses a focused laser beam to measure the particle size of granules, and PVM provides the microscopic images of the particles during the granulation process.

Other instruments, such as the FT-4 powder rheometer (Freeman Technology) and the TC Probe (C-Therm Technologies), and general differential scanning calorimetry (DSC) have also been used to measure the energies and thermal properties of dry powders and granules, according to Ali. “These techniques are useful because they provide information on the flowability, compressibility, and permeability of the granules, and can be used to address process analytical technology and quality-by-design requirements.