Paul Sheskey is a development leader at the Dow Chemical Company, Larkin Laboratory.

Paul J. Sheskey

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.

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.  

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. 

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 

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). 

 shows some typical designs for granulation. Keeping these mixing elements closer to the end of the extruder reduces attrition (4). 

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.) 

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.   

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 10

  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 

., 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 

. 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. 

 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 (2). 

Comparing foam and conventional wet granulation

A study at pilot-scale flow rates (20-40 kg/h) compared foamed-binder addition and direct liquid-injection on granulation (6). A methylcellulose binder (Dow, Methocel A15 PLV) was used at two concentrations, 6% and 11% (w/w), relative to a-lactose monohydrate powder. Two screws were tested in the work to produce differing axial compression characteristics (which was mentioned previously as an important factor for granule growth inside the extruder) with changing flow rate: one with a single pair of mixing elements producing lower axial compression (LAC) and a second with two pairs in series to provide a more restrictive flow path and higher axial compression (HAC). Notable differences between the two methods of granulation are summarized in 

. The granule properties from the study showed that comparable sizes and intragranular porosity were achieved by either method, provided appropriate conditions were used. The reduced requirement for liquid in the process was a comparable finding to that found with high-shear batch mixers (15). 

Table I: Differences between foamed and liquid binder addition on granulation. 

Wet granulation in twin-screw extrusion machinery has several key advantages over conventional methods, but to advance in acceptance for GMP production, its operations need to be better understood and challenges regarding process stability need to be solved. Continuous foam granulation is a new, robust technique that solves the process- surging issues that relate to poor powder wetting by conventional, liquid-addition methods. The high spreading tendency of foam in granulation, versus the immediate soaking nature of liquids, produces more uniformly wetted powders and increases the overall lubricity of the process, which benefits wear behavior of the machine and minimizes dissipative heating of the product. With comparable particle properties to conventional wet granulation, foam granulation gives formulators greater flexibility in achieving production goals.   

1. E.I. Keleb, A. Vermeire, C. Vervaet, and J.P. Remon, 

2. L. Tan, A.J. Carella, Y. Ren, and J.B. Lo, 

3. E.I. Keleb, A. Vermeire, C. Vervaet, and J.P. Remon, 

4. E.I. Keleb, A. Vermeire, C. Vervaet, and J.P. Remon, 

6. M.R. Thompson, S. Weatherley, R.N. Pukadyil, and P.J. Sheskey, 

7. W. Thiele, "Twin-Screw Extrusion and Screw Design," in 

, I. Ghebre-Sellassie and C. Martin, Eds. (Marcel Dekker, New York, NY, 2003), pp. 69-98. 

DOI: 10.1016/j.powtec.2012.05.045, May 29, 2012.  

12. B. Van Melkebeke, C. Vervaet, and J.P. Remon, 

13. N.O. Lindberg, C. Tufvesson, P. Holm, and L. Olbjer, 

14. M.R. Thompson, B. Mu, and P.J. Sheskey, 

16. M.X.L. Tan, L.S. Wong, K.H. Lum, and K.P. Hapgood, 

18. S.L. Cantor, S. Kothari, and O.M.Y. Koo, 

19. P. Sheskey, C. Keary, D. Clark, and K. Balwinski, 

is an associate professor in the Department of Chemical Engineering at McMaster University, Hamilton, Ontario, L8S 4L7, Canada, Tel: 905.525.9140, 

 is a principal research scientist at Larkin Laboratory, The Dow Chemical Company, Midland, Michigan.  

*To whom all correspondence should be addressed. 

Submitted: Sept. 6, 2012. Accepted: Sept. 28, 2012. 

Articles

The authors review developments in wet granulation using a twin-screw extruder.