Granulation has become an essential formulation choice for many pharmaceutical applications, owing to its superior physicochemical profile and improved handling conditions when compared to powders. Understanding and controlling granulation is essential to the production of high-quality pharmaceuticals, and optimizing processes to further streamline granulation can serve to create substantial improvements in a drug’s safety and efficacy.
Granulation, typically performed once powders containing the active pharmaceutical ingredient (API) and any excipients have been mixed together to a defined ratio, affords developers many advantages in terms of density, flowability, and uniformity. Various techniques have been developed to optimize the uniformity and efficacy of granulated products. Dry methods involve the use of applied pressure to compact powdered material, while wet granulation requires the introduction of a specialized binder to cause aggregate formation. Likewise, melt granulation relies on a meltable binding agent that amalgamates with the powder upon heating.
Affording superior process reproducibility and better process control than many other granulation techniques, fluid bed and melt granulation can be tightly regulated to produce uniform material with a specified particle size. These techniques represent an opportunity for drug developers to achieve appreciable efficiency gains in their processes, as well as measurable improvements in their final drug products.
There are various methods by which granulation can be achieved; choosing one requires a thorough understanding of the physicochemical properties of the drug, as well as the characteristics of any pharmaceutical excipients.
Dry granulation involves the use of applied pressure to bind particles together, and typically employs roller compactors or sluggers. Often used to compress moisture-sensitive materials, dry granulation is suitable for both continuous or batch granulation and is relatively inexpensive. A key disadvantage of this method is the high possibility for cross-contamination, since the process inevitably produces dust in the absence of any liquid material. To minimize this risk, it is essential to partner with a dry granulation provider who adheres to strict cGMP requirements.
Wet granulation methods offer greater scalability than dry granulation, enhanced reproducibility, and significant cost savings. They are also a preferred option for granulation of highly potent APIs, minimizing dust and affording manufacturers improved containment as a result. Various wet granulation methods exist, including steam granulation, which uses steam as the binding agent, and freeze granulation, a process which involves spray-freezing and subsequent freeze-drying. Fluid bed granulation is, however, the most popular technique, owing to its high reproducibility and scalability.
Melt granulation is the process of combining the pharmaceutical with a binder which melts at a relatively low temperature (50-90oC). Upon cooling, the material solidifies to form granules. This process is often chosen for water-sensitive pharmaceuticals; however, it can be unsuitable for heat-labile drugs such as proteins or peptides.
The Advantages Of Fluid Bed Granulation
During fluid bed granulation, high- velocity air is used to suspend powdered material within a fluid bed granulator. This specialized, multi-purpose piece of equipment is capable of mixing, granulating, and drying, obviating the requirement to use separate instrumentation for each stage of the process. Designed to introduce the air stream into the bed from below, the fluid bed granulator expands the bed upward to provide high heat and mass transfer surface area. This process can also be microwave-assisted to provide much faster drying rates and lower operating temperatures.
Next, a binder is sprayed onto the powder, causing the particles to stick together and form granules. This occurs via a stage wise process of moistening and solidifying to give rise to agglomerates. A wide variety of binders can be employed, including aqueous or organic solvents, as well as dissolved polymeric materials.
The granules are subsequently dried using hot air. Since the temperature of the air flow can be tightly regulated, fluid bed granulation is highly suitable for heat-sensitive materials.
In addition to reduced costs and space requirements as a result of combining multiple processes within the same specialized instrument, fluid bed granulation offers many further advantages. Firstly, it is highly reproducible since the capacity to control the air flow and the ability to dictate the rate at which the binder is sprayed onto the powdered material afford extremely tight control over granule size. Drying is fast and homogeneous, with no problematic hot spots since the granules do not encounter the drying surface but are instead suspended. Fluid bed granulation is easier to scale and affords more accurate prediction of product attributes than high- shear applications. Furthermore, timings can be normalized between manufacturing runs to ensure the production of highly uniform material.
The granulation process is typically followed by steps such as sizing, blending, and compression. Of these, sizing can be especially costly and time-consuming. Techniques suchas sieve analysis, image analysis, and laser diffraction all require the use of specialized equipment and necessitate the granulation process to be paused while sampling is carried out. The incorporation of fluid bed granulation into pharmaceutical manufacturing processes can often eliminate sizing through enhanced particle size distribution (PSD) control.
Fluid Bed Granulation Process Engineering
Wet granulation involves four key mechanisms or rate processes that take place simultaneously and continuously inside the granulator. These are wetting (also referred to as nucleation), growth, consolidation, and breakage. The interaction between these different mechanisms determines the final size distribution of the granulated product, in addition to controlling important attributes such as density and porosity.
The ability to control key process parameters that directly impact these mechanisms is essential to successful granulation. In terms of air flow, these include the porosity of the distribution plate and the bed pressure drop, while for the granulation and drying process, critical factors are the inlet air temperature and relative humidity, solution spray rate, and atomization air pressure/flow. It is also important to consider exhaust air conditions and variables such as chamber pressure, fill volume, and filter pressure drop.
The size, density, porosity, strength, and compressibility of granules will all be controlled by these factors, along with flow properties, moisture content, and degradation. One of the most time-consuming stages of fluid bed granulation is drying, a step which can greatly impact the overall process efficiency.
Since residual moisture content can have serious adverse effects on the physical and chemical stability of the product, understanding the drying process is of fundamental importance.
Drying consists of three phases. Phase 1 occurs as the product bed and equipment warm up, during which surface water is removed at an increasing rate. During phase 2, a constant rate of surface water removal takes place, accompanied by the migration of small amounts of intra-granular water to the granule surface. Phase 3 involves the removal of bound water from the granule surface and is dictated by the rate of intra-granular water migration.
When implementing an effective fluid bed granulation process, it is important to determine acceptable final LOD limits or range and to identify upper temperature limits.
A popular technique for granulating poorly water-soluble drugs, melt granulation combines a powdered API and pharmaceutical excipients with a liquid or meltable binder in an extruder. A more scalable method than dry granulation, resulting in a more consistent product, melt granulation avoids the need for drying, a feature which can enhance process efficiency.
It is highly important to understand the nature of the binder to be used during melt granulation since this can have a significant impact on the nature of the granules which are produced. When the binder particles are smaller than the powder particles, the binder spreads over the surface of the powder particles to produce large granules as a result of distribution and coalescence. In contrast, when the powder particles are smaller than the binder particles, the powder particles adhere to the surface of the binder to produce granules which grow in layers. The type of granulation which occurs will impact the properties of the resulting product.
AbbVie For Granulation
A range of granulation capabilities exist throughout AbbVie’s manufacturing network, including dry, wet, and melt granulation at different scales. With extensive expertise in granulation methods, we also offer biologics manufacturing, cold chain, and packaging. AbbVie offers late- phase clinical and commercial spray and melt granulation manufacturing in the U.S. and Europe, with sites in Ludwighaven, Germany; Cork, Ireland; Barceloneta, Puerto Rico; and Chicago, Illinois.
AbbVie Contract Manufacturing is an embedded CMO with pharmaceutical expertise that draws on 40 years of experience with developing, manufacturing, and scaling a variety of drugs. We leverage this wealth of experience, combined with cutting- edge equipment at varying scales and the latest modelling and simulation tools, to enable a broad range of tech transfers. Contact AbbVie Contract Manufacturing to discuss your granulation requirements.