Advanced Granulating Technology Improves Process Efficiencies

About 70 percent of pharmaceutical products are solid-dosage forms — tablets, capsules, oral powders, and powders for solutions or suspensions. With about 36 to 40 percent of industry costs resulting from manufacturing, the granulation process plays an increasingly important role in production as it provides the primary physical modification of the bulk ingredients leading to all downstream processes.

As has been the case in recent years, energy, water and labor costs continue to be major concerns for pharmaceutical processors, and granulation impacts all of these costs. According to the U.S. Department of Energy, the U.S. pharmaceutical industry consumed almost $1 billion in energy annually through 2008. As energy costs have risen sharply since then, that dollar amount has jumped year over year.

In 2005, the average pharmaceutical company used 22 million cubic meters of fresh water, 17 million of which is sourced mainly from municipal water supplies (59 percent) or wells (40 percent). As energy costs have risen, there has been a corresponding increase in the cost to manufacture and transport water into and out of manufacturing plants.1

More effective granulation can reduce both energy and water use in several ways. First, new equipment is simply more efficient that old equipment. Second, improvements in equipment design, process design and materials transfer are shortening process cycle times and, in many formulations, reducing the water volume needed for effective manufacture.

With pharmaceutical companies using more exotic, costly APIs and introducing new dosing, finding the right granulation process and appropriate equipment is more important than ever. Many of the newest granulation applications are being used for rapid-release dosing, melt granulations, pelletization and effervescent granulation.

Other process innovations are being used to improve quality and reduce waste in well-established dosing forms such as sustained-released microspheres. Of course, continuous process manufacturing remains something of a Holy Grail for pharmaceutical manufacturers. Improvements in equipment and processes continue to move the industry toward this goal in steps that allow for cost control, quality control and cGMP compliance.

How and Why

Perry’s Chemical Engineer’s Handbook defines granulation as “any process where by small particles are gathered into larger, permanent masses in which the original particles can still be identified.” Granulation is both a physical and a chemical process. It is the first step in which multiple formulation components are combined, and it’s usually the most complex and difficult process to control during manufacturing.


The main goals of granulation are to improve flow and compression characteristics of the blend, to allow the rapid breakdown of agglomorates to maximize the available surface area and aid in the dissolution of the active drug, and to prevent component segregation. But there are any number of other reasons, and sometimes multiple reasons, for granulation such as:

• Increasing uniformity of API distribution in the product;

• Increasing the bulk density of a product;

• Improving flow rate and rate uniformity;

• Facilitating metering or volumetric dispensing;

• Reducing dust; and

• Improving product appearance.

Equipment Advances

To gain maximum advantage of capital equipment investments, producers must look at their systems holistically. Cost analyses have proven time and again that piecemeal systems increase operational costs through increased labor requirements, product loss and quality failures.

High shear granulation in combination with a fluid bed, which has been in commercial use for more than 60 years and is the most widely used granulation equipment in the United States, offers a number of advantages, including processing at ambient temperatures for thermosensitive materials and the production of low-density, free-flowing granules. The combination of equipment allows two forms of granulation: fluid bed and high shear.

Fluid Bed

A drug substance can be added as a solid or by a solution. Granules produced in a fluid bed system are porous and have a loose structure, enhancing their wettability and reducing their bulk density compared to those produced via high-shear granulation.

The most advanced fluid bed dryers employ tangential spray technology. Instead of the traditional top-down nozzle position, tangential spray systems put the nozzles in the bowl’s side walls at specific angles. This creates several advantages. First and most obvious is that tangential positioning means the machine does not need to be as tall as a top-down unit. This gives manufacturers flexibility with their floor plan.

More importantly, tangential technology provides more uniform coverage in a shorter amount of time because the spray is working with the airflow and not against it. This technology is also capable of handling batches of more than 475 kg, further shortening processing times.

The trend toward using high-potency, low-volume APIs such as those found in many cancer drugs and hormone treatments is driving manufacturers toward closed systems. These systems link mixing, fluid bed drying, sieving, milling and blending together. This yields several benefits:

• It reduces dust, improving housekeeping;

• It reduces transfer handling and product loss;

I• t improves worker safety; and

• It improves quality and consistency.

Tangential fluid bed technology is also well-suited to closed-loop processing. The nozzle position means the bowl can be equipped with an outlet valve that allows product to move directly into the sieve without removing the bowl. This keeps the product contained during transfer.

High Shear

In the meantime, energy-efficient, water-efficient batch systems are helping producers contain costs while reducing batch process times. High-shear mixers typically require less water than low-shear mixers. A high shear mixer with a curved bowl has much better compression capabilities than one with a flat bowl. Better controls over impeller rotation speeds and method of liquid addition also influence the liquid requirements.

Another new technology — the single pot system — is not really new, but it is one that is just now starting to find acceptance in the United State. Long used in Europe, single-pot systems are well-suited to closed systems because they incorporate mixing, granulating and drying in a single, contained vessel.

Advanced single-pot systems employ vacuum and a carrier gas that grabs moisture particles. This reduces drying time by 50 percent compared to drying by a heat jacket alone. The latest systems also use microwave drying, which can further reduce drying times by another 50 percent over gas only.

Many manufacturers are reluctant to change existing granulation systems to single-pot systems because they do not want to have to go through Food and Drug Administration certification for a “working” process. Single-pot systems, however, will work well in new facilities or for manufacturers that are adding new production in an existing space.

Dry granulation batch systems are gaining acceptance in the market. These systems typically require just 3 to 10 percent of the energy used in wet granulation systems like fluid beds.

Technology Advances

Single-pot and closed-loop systems bring with them additional challenges for manufacturers, particularly in the area of process monitoring. Chemical imaging (CI) is an emerging technology that integrates conventional imaging and spectroscopy to attain both spatial and spectral information from an object.

Vibrational spectroscopic methods such as near infrared (NIR), Raman spectroscopy and acoustic detectors have significantly improved the detection and knowledge of process endpoints in closed systems. These technologies are helping manufacturers comply with current guidelines and the Process Analytical Technology (PAT) approach. CI is fast, nondestructive and noninvasive, which makes it valuable in process applications.2

Twin-screw granulation, while it’s been applied for years in the food and chemical industries, is the next step forward in continuous process wet granulation. Extrusion granulation was first used in pharmaceutical manufacturing in the mid-1980s, but was never widely adopted by the industry.

Co-rotating or counter-rotating screws can be used for granulation. A dosing system supplies powder to twin-screw extruders. The powder is conveyed, agglomerated with a granulation liquid, dried using microwave or radio-frequency means, and then discharged. Extrusion granulation is flexible and cost-effective, and it can be used in a continuous manufacturing process, moving manufacturers closer to continuous processing.

Additionally, fully automatic clean-in-place (CIP) and wash-in-place (WIP) units are available for all the above mentioned systems.


1. GlaxoSmithKline. Corporate responsibility report. 2005. Available from: URL:

2. Bertuzzi G. Granulation: evolving slowly but surely. Pharmaceutical Technology Europe. 2010;22(6)

About the author:

Elle Nolte is manager of process technologies and services for L.B. Bohle LLC in Warminster, Pa. He can be reached at

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