Mechanical Control with Foam Granulation Well-Suited for Pharmaceutical Manufacturing - Pharmaceutical Technology
Mechanical Control with Foam Granulation Well-Suited for Pharmaceutical Manufacturing
Foam granulation is much easier to control under mechanical dispersion conditions, which is where most industrial processes operate.

Pharmaceutical Sciences, Manufacturing & Marketplace Report

Although direct compression without the need for any granulation step is generally preferred for solid dosage manufacturing, often the properties of the API require that some form of granulation be used. Foam granulation is a type of wet-granulation process that is attracting significant attention because a foamed liquid binder can often be added more quickly without over wetting, allowing shorter processing times and more controlled granulation processes than can be achieved using traditional spray granulation techniques, according to Karen Hapgood, head of the Department of Chemical Engineering at Monash University in Australia.

“The inventors of this technology—Paul Sheskey and Colin Keary (1) from Dow Chemical—took a common often problematic characteristic of standard pharmaceutical binders—foaming—and turned into a terrific advantage,” she says.

In foam granulation, air is incorporated into an aqueous solution of a typical water-soluble binder, such as hydroxypropyl methylcellulose (HPMC), to a form a foam that resembles shaving cream. The increased surface area of the foam compared to the liquid solution aids in enhanced distribution of the binder throughout the powder bed containing the formulated solid dosage drug. Hapgood and her colleague Melvin Tan have been investigating the similarities and differences between traditional spray granulation and foam granulation, what might be the cause for the differences, and particularly how foams and liquids interact with powders during granule formation.

Figure 1. Initial stages of foam penetration (left) and drop penetration (right) into a static powder bed. Figure courtesy of Karen Hapgood.

“In light of the existing knowledge on spray nucleation, we initially thought that the foam might be able to more quickly wet, penetrate, and sink into the powder than a drop of liquid. The assumption was that the foam would be spread over a larger drainage area and allow the liquid to flow more easily into the powder, which would in turn imply the existence of more important interactions at the powder-foam interface to aid nucleation,” Hapgood explains. They tested the idea by measuring the time required for complete penetration of the fluid into the powder for small drops of liquid and small “blobs” of foam (see Figure 1) produced from a hand-held foam dispenser (2).

What they found, however, was that the foam penetrated faster than the drops in some cases, but slower in others. In fact, in many cases the foam penetration time was very long—up to 2000 seconds per gram of fluid, according to Hapgood. 

“Because the granulation process is quite rapid, liquid dispersion must occur within a few seconds; therefore, the improved liquid dispersion behavior observed with foam granulation is unlikely to be due to faster wetting of the fluid. In addition, it can be concluded that foam nucleation is not controlled by wetting at the liquid powder interface,” Hapgood observes.

Based on their results, she and Tan determined that foam nucleation was most likely controlled by mechanical dispersion of the foam fluid through the powder during agitation of the powders (3). “We also confirmed that the foam was able to nucleate more powder per unit mass of fluid; i.e., foam has a higher nucleation ratio, which supports the results of the Dow researchers, who found that foam granulation requires less liquid to achieve the same extent of granulation (1),” she adds.

Next, Hapgood and Tan carried out experiments that imitated the initial stages of the foam granulation process by adding small quantities of a 4% HPMC foamed fluid to a moving bed of lactose powder in a five-liter mixer granulator (4). The addition of only a small quantity of liquid allowed formation of some nuclei granules while avoiding significant growth and breakage of the granules, according to Hapgood.

“These experiments showed that the foam sat on the powder surface for a significant period of time. In poorly agitated beds, the powder looped around and around on the top of the ‘bumping’ powder; once the agitation was increased, however, the foam was dispersed extremely quickly to achieve ‘roping’ or torroidal flow,” she says.

Furthermore, when the researchers conducted full granulation batches comparing spray granulation and foam granulation under the same conditions, they found that foam addition produced granules with a narrower size distribution and fewer “lumps” (granules larger than 2 mm compared to those obtained using spray addition. 

“If the agitation were low, some lumps formed with foam granulation, but they were easier to mechanically disperse because the energy required to break up a single drop has already been overcome during the foam-formation stage. In addition, foam nuclei are slightly larger than those formed during spray granulation for the same amount of fluid, and are, therefore, less saturated, which makes any foam lumps easier to break up and disperse,” Hapgood observes.

“Based on these tests, we concluded that the key practical difference between spray and foam granulation is that spray granulation requires a lot of effort to keep it in the drop-controlled regime while foam granulation is much easier to control under mechanical dispersion conditions, which is where most industrial processes operate,” she continues.

Because foam granulation was first developed less than 10 years ago, the technology remains in its infancy with respect to commercial use. Hapgood does note, however, that several pharmaceutical companies are investigating foam granulation as a possible process option in their formulation and process development decision trees.

She also points to continuous granulation in twin screw granulators (TSGs) as not only a major area of interest in the industry, but a potential application where foam granulation could play an important role. “Distributing the liquid uniformly in the TSG is tricky, because there is only 5–20 seconds of mixing time before the granules exit the system. The use of foam might be ideal for this situation, because less liquid is required to distribute the binder when using foams, and foams mix and disperse more readily when there is good powder agitation and shear,” explains Hapgood. “I think this continuous granulation work is very promising and is an area that I hope to be able to follow up in future,” she asserts.


  1. C. M. Keary and P. J. Sheskey, Drug Dev. Ind. Pharm. 30 (8) 831-845 (2004).
  2. M.X.L. Tan and K.P. Hapgood , Chem. Eng. Res. Design 89 (5), 526-536 (2011).
  3. M.X.L. Tan and K.P. Hapgood, AIChE Journal 59 (7) 2328-2338 (2013).
  4. M.X.L. Tan, et al., Drug Dev. Ind. Pharm. 39 (9), 389-400 (2012).
Source: Pharmaceutical Sciences, Manufacturing & Marketplace Report,
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