The aqueous foamed binder used in foam granulation is comprised of a high volume of gas dispersed within a liquid containing
foamable excipients, thus forming an unstable, semi-rigid structure. Effective excipients for pharmaceutical granulation are
cellulose-ether species that promote high foaming activity and act as binders in the process. Many approved nonionic, polymeric
excipients are also suitable foaming agents. The foam liquid may include additives (e.g., polymeric species for binding or
coating and particles, such as APIs, glidants, and disintegrant aids) as long as they do not interfere with its preparation.
Semirigid foams characteristically exhibit closely packed bubbles or a polyhedral morphology depending on the gas-volume fraction
although a minimum of 64% (v/v) gas is required for the foam to display some degree of rigidity. The volume fraction of gas
present in foam is often referred to as its foam quality (FQ). For granulation, FQ is generally kept in a range of 75–95%.
Foams that are too wet (< 75% FQ) lack adequate stability to spread well and often simply collapse on the surfaces of processing
equipment. Very dry foams (> 95% FQ) occupy very large volumes of space (which complicates their addition into the confined
process); exhibit very high inherent viscosities (as much as 105 times that of its contained liquid); and more readily collapse in the presence of shear than wetter foams (14).
Foam granulation was first introduced by Keary and Sheskey for high-shear batch mixing of pharmaceutical ingredients (15).
This study demonstrated that less binding liquid was required and that the rate of foam addition could be much higher in comparison
to spray wetting. The lower requirements of binding liquid were explained in the staticbed penetration studies of Tan et al., which looked at saturation characteristics of foam versus dropwise wetting with lactose and glass ballotini powders (16).
These studies observed that more binder mass was absorbed by these powders by foam as opposed to dropwise addition at any
given time, and as a result, granule nuclei were 40% larger. Foams of higher FQ were more slowly absorbed due to slower foam
coarsening and slower drainage of its contained liquid into contacting powder (14, 17). Several studies of foam granulation
for high-shear batch mixers have been reported (17–21).
Figure 2: Typical equipment layout for foam granulation showing: (1) twin-screw extruder, (2) powder feed-port, (3) gravimetric
feeder for powder excipients, (4) side stuffer, (5) mechanical foam-generator, and (6) foam feed-tube.
Continuous foam granulation with a twin-screw extruder was introduced in a case study comparing the technique to the conventional
liquid addition method (6). A successful methodology to metering such foam into the machine required recognizing its solid-like
behavior and using approaches commonly employed for feeding bulk solids rather than liquids. An auxiliary unit, known as a
side stuffer to the extrusion industry, was found suitable for feeding foam. The side stuffer is readily available commercially,
and the physical setup and control software of most extruders can be configured to accommodate it. A typical extrusion setup
with the side stuffer and foam generator is shown in Figure 2. The side stuffer is a miniature, twin-screw auger that mounts to the side of the main extruder and conveys materials into
a specified zone of the process. Due to the drag-flow action of the rotating screws in the side feeder, foam is forced into
the passing formulation within the main extruder and partially collapses upon contact, while the remaining foam forms a layer
between the powder and extruder barrel. Figure 3 highlights the conceptual differences between liquid injection and foam addition from a cross-cut view of the extruder. The
mechanism of foam wetting inside the extruder is still under study. A two-stage model proposed in a recent publication was
based on how foams prepared from liquids of different viscosities and having different FQ collapsed and drained under different
shear conditions as well as how they affected granule properties from the extruder (14). A pressure-driven wetting stage is
thought to occur at the point of entry where the foam enters the process, with stiffer foams showing greater resistance to
immediately collapsing upon contacting the non-wetted formulation. The remaining, uncollapsed foam pushes the powder aside
to form a layer above. The subsequent shear-driven wetting stage appears governed by the response of foam to shear; layers
of stiffer foam collapse more readily under mechanical shear to wet the powder beneath while wetter foams show greater resistant
collapse under mechanical shear by establishing more stable morphologies comprised of smaller bubbles.
Figure 3: A cross-sectional view of the twin-screw extruder partially filled with powder excipients (in blue) shows the differences
in configuration used for (a) directly injecting liquids versus (b) introducing foamed binder into the granulation process.
From a practical, operational standpoint, the method of foam granulation:
- Avoids process surging in a twin-screw extruder due to the high coverage area of foam over the powder during wetting
- Simplifies process start-up because full operation rates can be immediately achieved, as opposed to liquid injection, in which
powder flow must be slowly increased to prevent motor overload
- Reduces machine wear, as indicated by the extruder no longer experiencing the loud knocking noises indicative of screw deflection
caused by uneven powder flow.
These observations are thought to be related to the two-stage wetting mechanism previously described, which causes the powder
to become immediately isolated from the barrel wall by a layer of foam, at least until it is well wetted. The powder in this
case is steadily saturated with the binder over a much larger area of contact than in direct liquid addition, which minimizes
the binder's local concentration in the porous matter. The lubricating feature of foam granulation, in which the foam layer
isolates the powders from the barrel wall until uniformly wetted, is an important point to be stressed for extrusion processing.
The lubricity of conveyed solids affects both power consumption by the machinery as well as the exiting temperature of granules