Foam Granulation

The authors review developments in wet granulation using a twin-screw extruder.
Mar 02, 2013

As a result of changing philosophies towards continuous manufacturing, new equipment is being introduced into pharmaceutical production facilities. The twin-screw extruder is an example of such equipment for use in wet granulation. The authors review developments in wet granulation using a twin-screw extruder; lay out the issues with wetting in this machine; and introduce a novel technique, foam granulation, that uses the twin-screw extruder to fully satisfy the unique needs of granulation.


PHOTO CREDIT: M. THOMPSON.
The twin-screw extruder provides highly consistent granulates due to its continuous operation and closely confined flow path, which requires that all particles experience a similar shear history. The intensive mixing of the twin-screw extruder allows lower optimal liquid concentration for granulation while producing denser granules for both placebo formulations and highly dosed drugs in comparison to a high-shear batch mixer (1, 2). As a result, drying and milling operations may be significantly reduced with use of this machinery in solid oral-dosage production.

The binding liquid in wet granulation has a profound influence on product granule properties (3–5) and affects the friction between conveyed powders and the barrel wall inside the extruder, which affects power consumption and the exiting temperature of granules (2, 6). There are crucial issues to be solved in regards to introducing liquids into this type of machinery to obtain rapid and uniform wetting of excipients so that the process exhibits stability in operation, boundaries become immediately lubricated to reduce equipment wear and granule heating, and high quality granulates are obtained.

Twin-screw extruder function

A common variant of extruder used for granulation is the fully intermeshing, co-rotating twin-screw extruder (7). Differences between vendors are largely based on the available internal volume of the machine (often described by the ratio of the outer diameter to inner diameter of screw elements) as well as the screw diameter, both of which can significantly affect granulate properties in both granule size and intragranular porosity (8). The machine is highly modular, making it a flexible platform for continuous manufacturing of different products during its lifetime of service to a company. The intermeshing region between the two screws creates a self-wiping action that minimizes material accumulation within the machine but also provides a complex flow path for powders to mix and consolidate. For wet granulation, the die end of the extruder is generally open to collect granules without excessive consolidation.


Figure 1: Characteristic screw designs used in twin-screw extruders for wet granulation. Screws displayed correspond to literature referenced in this article: (a) ref. 11, (b) ref. 4, (c) ref. 6, and (d) ref 6. Powders enter at the extreme left-hand side and arrows indicate points of liquid addition. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Wet granulation inside the co-rotating twin-screw extruder is a starve-fed process, meaning that the available internal volume of the machine is never completely filled with material during operation. This modus operandi is important to extrusion because it minimizes dissipative heat build-up in conveyed drug formulations as it limits compression against the barrel wall, it decouples the parameters of output rate and screw speed to give formulators more control over their process, and it more readily allows the downstream addition of materials (solids, liquids, or gases) because the system is not pressurized except for small mixing regions. The zones of the screws that are starved experience dominant drag flow, in which powders are pushed downstream by the rotating flights of conveying-type elements. These screw elements have been found to contribute little to granule growth (5, 9). In fact, screw designs using only conveying elements show very poor distribution of the binding liquid within exiting solids (10). It is rare, however, that a screw design is completely comprised of conveying elements or that the entire length of the machine is ever fully starved. Significant granule growth requires the inclusion of pressure-driven mixing zones, which are necessarily fully filled as powders are squeezed through these sections. Kneading blocks and comb (i.e., chopping) elements are examples of mixers commonly used in sparing numbers along the screw length to produce granule growth along with minor attrition (5, 9, 11–13). Figure 1 shows some typical designs for granulation. Keeping these mixing elements closer to the end of the extruder reduces attrition (4).

Powder flow rate is one of the most significant parameters influencing the extent of granule growth, with higher outputs producing larger granules. The effect is caused by the higher volumes of powder that build up in front of pressure-driven mixing zones as flow rate increases, producing larger axial compressive forces on the particles present. In fact, it has been shown that the dispersion of binder within poorly wetted mass can be improved for granulation if the screw design and flow rate are adjusted to provide appropriate compressive forces (6). The influence of flow rate on granule growth, however, is not often seen in smaller extruders or highly starved processes (4). Increasing screw speed has less influence on granule size but generally increases the number of chopping events provided by mixing zones to reduce the occurrence of oversized particles (4, 6, 9). For a fixed flow rate, increasing the screw speed will reduce the volume of powder that fills the conveying screw elements, resulting in lower power consumption by the process.

Among the published studies for wet granulation, a crucial point that is rarely mentioned, yet widely known to the pharmaceutical industry, is the difficulty of uniformly wetting a formulation in an extruder. The problem arises due to the earlier mentioned closely confined space inside the extruder, which results in the liquid injection port being in immediate proximity to the powder flow. This confinement prevents atomization of the binder solution into micro-sized droplets prior to contacting the powder solids, as is done in high-shear batch mixers. As a result, regions of the powder become oversaturated while others remain virtually dry. This issue was highlighted in the industrial-oriented article by Shah, who reported process surging, though motor overload events are also common (11). Shah demonstrated several strategies related to screw design and the sequential addition of smaller liquid quantities into the process as means to minimize surging occurrences. Such changes greatly increase the complexity of operating the extruder and do not eliminate the root cause of the problem. Alternatively, a new solution called foam granulation uses the unique behavior of aqueous foam to cause rapid spreading of the binding liquid over a large area of the powder during wetting.