Charlie Martin is a general manager at Leistritz North America

Charlie Martin

Extrusion technology is a highly advanced, standard manufacturing methodology that has been used for more than 70 years. Twin-screw extruders are used in the plastics industry to mix polymers with additives and fillers for nearly every plastics product we encounter, including plastic pipes, garbage bags, and carpet fibers.  

In recent years, the continuous extrusion process has been applied successfully to pharmaceutical formulations by downsizing sound, established continuous manufacturing techniques. In addition to being a proven manufacturing process, continuous extrusion meets the goal of the US Food and Drug Administration's process analytical technology (PAT) initiative for designing, analyzing, and controlling the manufacturing process through quality control measurements during processing.  

Twin-screw extruders are also used to process complex mixtures for a variety of controlled-release products with pharmaceutical polymers matched to the thermal sensitivity of the drug. Hot-melt extrusion (HME), in particular, involves melting materials, mixing them with active pharmaceutical ingredients (APIs), pumping them through a die, and sizing/cooling them into a shape.  

Interest in pharmaceutical HME has greatly increased since the early 1980s as demonstrated by a steady increase in related patents. But it has only been in the past 10 years or so that the pharmaceutical industry has begun to influence twin-screw extruder designs by prompting equipment modifications for regulated manufacturing environments. As the technology is understood, embraced, and applied in this new application arena, extrusion is being recognized as a better approach as compared with traditional batch methods. An HME system is tailor-made for designing, analyzing, and controlling a manufacturing operation through on-line measurement to ensure final product quality, which makes it ideally suited for PAT. 

Benefits of HME include the absence of solvents, fewer processing steps, and lower manufacturing costs. Without exception, if the formulation is amenable, the continuous extrusion process is also more consistent and repeatable compared with batch processing.  

HME offers advantages in techniques as well. Molten polymers are specified to function as thermal binders and act as drug depots and/or drug-release retardants upon cooling and solidification. Solvents and water are generally not necessary for processing when using HME, which results in fewer processing steps. Expensive drying equipment and time-consuming drying steps also can be eliminated with HME. In addition, a twin-screw extruder acts as an efficient devolatilization device and can be configured to remove more than 40% of volatiles during processing. 

The intense mixing associated with the inter-screw mass transfer characteristics inherent with twin-screw extrusion results in highly efficient distributive and/or dispersive mixing, and therefore a more uniform product. The molecular level mixing often achieved by HME has improved the bioavailability of many drug substances, especially for those with low water solubility.   

The short residence time associated with HME, as compared with a batch process, is beneficial for many heat- and shear-sensitive compounds. The HME process can be designed to limit exposure to elevated temperatures to just a few seconds to avoid the degradation associated with both time and temperature. Downstream feeding of APIs also avoids the shear effects associated with melting the polymer, which is the highest shear region in the HME process section.   

The major differences between pharmaceutical and plastics extrusion machinery is that the metallurgies for parts that wet the materials are specified to be nonreactive, nonadditive, or nonabsorptive with the pharmaceutical product. In addition, the equipment used for pharmaceutical extrusion is configured to meet cleaning and validation requirements associated with a good manufacturing practice (GMP) environment. Otherwise, the unit operations performed for pharmaceutical and plastics processes are identical. 

Twin-screw extruder process materials are bound by screw flights and barrel walls (see Figure 1). Rotating screws, driven by a motor, impart shear and energy into the materials being processed. Inside any extruder, a number of process tasks are performed such as feeding, melting, mixing, venting, and developing die and localized pressure. Control parameters include screw speed (rpm), feed rate, process-section temperatures, and vacuum level (for venting). Typical parameters that are monitored include melt pressure, melt temperature, and motor amperage (torque). In-line optical sensors can be used to monitor the quality of the melt stream. 

Figure 1 (All figures are courtesy of the author.) 

Programmable logic controllers (PLC), in combination with various control software packages, are specified to fulfill FDA 21 

 Part 11 regulations. These database packages offer sophisticated security and backup features that meet the intent of this regulation. 

A common extrusion term is "length to diameter ratio" or L/D. This term expresses the length of the screw divided by the diameter. For instance, an extruder that is 1000 mm long with a 25 mm screw diameter has a 40:1 L/D. Typical extrusion process lengths are in the 20 to 40:1 L/D range, or longer. Extruder residence times are generally between 5 s and 2 min, depending upon the type of extruder, L/D, and how the extruder is operated with regard to feed rate and screw rpm (see Figure 2). 

Figure 2 (All figures are courtesy of the author.) 

Another common term is "outside diameter of the screw" or OD. For instance, when referring to a 20 mm extruder, OD refers to the outer diameter of each screw for a twin-screw extruder. The inside diameter, or ID, is the OD less the flight depth multipled by two. 

The flight depth of the screws is an important design parameter. A deeper flight depth increases the free volume in the machine but limits the torque transmittal. 

Finding the optimum balance between free volume and torque is important because the balance directly impacts attainable throughput rates (high or low), as well as the energy that is imparted into the materials. Twin-screw extruders can process as little as a 20-g batch and more than 5000 kgs/hr. 

Figure 3 (All figures are courtesy of the author.) 

The screws are the heart of any twin-screw extruder and the design directly impacts the quality of the dosage form. Screw elements are flighted for material transport, and nonflighted to create shear regions for melting or mixing. Solids conveying and melting occurs early in the process section. Screw elements for mixing and devolatilization are applied as required. Discharge elements then build and stabilize pressure before discharge. Screws are typically segmented and assembled on splined shafts. One-piece construction is also possible for improved cleaning and validation purposes. 

Screw designs can be shear-intensive and/or shear-passive with compounding efficiencies defined in terms of dispersive and distributive mixing. In dispersive mixing, the particles are broken down. Dispersive mixing elements result in the materials experiencing extensional- and planar-shear effects. In distributive mixing, the materials are uniformly blended but not broken down. Distributive mixing elements force high-melt division rates with significantly less extensional and planar-shear effects. Distributive mixing is often implemented for mixing heat- and shear-sensitive APIs with minimal degradation (see Figure 4).  

Figure 4 (All figures are courtesy of the author.) 

The cross-section of the barrel for a twin-screw extruder is characterized by a barrel opening in the shape of a "figure 8." Barrels for twin-screw extruders can be either one-piece or modular and can be configured for downstream feeding and venting. Barrel sections are heated by electric heaters or liquid. Barrel-cooling facilitates a temperature set point to maintain the desired melt viscosity within the process section. Extruder barrel(s) are typically cooled by liquid, and sometimes air. The most effective heat-transfer design uses axial cooling bores inside the barrel and close to the process melt stream (see Figure 5).  

Figure 5 (All figures are courtesy of the author.) 

The segmented design of the process section enables specific screw and barrel geometries to be matched in a calculated and iterative manner to the unit operations that are performed in the process section. Modularity also makes the twin-screw extruder a flexible and powerful research tool when developing new applications for dosage forms. 

There are two distinct families of twin-screw extruders: high-speed energy input (HSEI) twin-screw extruders, which run up to more than 1200 rpm; and low-speed late fusion (LSLF) twin-screw extruders, which run up to 50 rpm. HSEI twin-screw extruders are primarily used for compounding, reactive processing and/or devolatilization. By contrast, LSLF counterrotating twin-screw extruders are designed to mix at low shear and pump at uniform pressures but are often inadequate to perform energy-intensive processing.  

HSEI twin-screw extruders are mass-transfer devices used for intensive mass-transfer operations such as compounding, devolatilization, and reactive extrusion. HSEI twin-screw extruders are available in co-rotation and counterrotation and have top-end screw speeds from 300 to more than 1200 screw rpm.  

HSEI twin-screw extruders are starve-fed with the output rate determined by the feeder(s). The extruder-screw rpm is independent from the feed rate and is used to optimize compounding efficiencies. Because the pressure gradient is controlled and remains at zero for much of the process, materials can be introduced into downstream barrel sections, typically by a twin-screw side stuffer that "pushes" materials into the extruder screws. Downstream introduction of heat- or shear-sensitive APIs can be particularly beneficial to avoid high-shear regions and minimize residence time exposure. The controlled pressure profile also facilitates venting. 

For a co-rotating twin-screw extruder, the screws are termed "self-wiping," as the opposing surface velocities in the intermesh regions cause the material to follow a figure 8 pattern. In co-rotation, the rotational clearances typically limit the lobe count to two for standard flight depths (see Figure 6).  

Figure 6 (All figures are courtesy of the author.) 

In counterrotation, the surface velocities of the screws in the intermesh region work in the same direction which results in materials being forced between the screws where extensional mixing occurs, referred to as the calendar gap. Geometric characteristics inherent with counterrotating screw designs makes it possible to have up to six lobes at the same flight depth as bilobal co-rotating designs, which results in more mixing events for each screw rotation (see Figures 7 and 8). 

Figure 7 (All figures are courtesy of the author.) 

The LSLF counterrotating, intermeshing twin-screw extruder is designed for gentle melting and mixing combined with a narrow residence distribution and high-pressure generation capabilities. The screw flights converge in the same direction in the nip region, causing the gap between the flights to be small and minimizing leakage from one screw channel to the next. Mixing occurs between the screws as the material experiences shear effects in the calendar gap. This device can be used for shear- or temperature-sensitive materials that do not require intensive mixing. 

Figure 8 (All figures are courtesy of the author.) 

Generic twin-screw extrusion related formulas

Shear forces result in mixing, which is the primary function of most HSEI twin-screw extruders. Shear rate describes the velocity gradient between two surfaces moving at different speeds. For a HSEI twin-screw extruder, this is a function of screw outside diameter, screw speed, and overflight gap.  

 Peak shear rate = (π  × D  × n)/(h   × 60) 

 is the overflight clearance. So for a HSEI twin-screw extruder with 27 mm OD screws and an overflight gap of 0.1 mm operating at 600 rpm, the following applies:  

Peak shear rate = (π  ×  27  ×  600)/(0.1  ×  60) = 8478/s

 This equation does not take into account extensional shear, an important component for dispersive mixing but does provide a usable benchmark for comparison and troubleshooting purposes. 

The magnitude of the applied stress that the materials experience is a function of the shear rate and viscosity, and is reflected by this formula: 

Barrel temperatures are used to manage the viscosity of the melt, which impacts the mixing quality. Cooling is often used to raise the viscosity (Ec), which facilitates dispersive mixing in a HSEI twin-screw extruder.  A smaller E

 is preferred if distributive mixing is the goal. 

 Specific energy (SE) is the amount of power that is being input by the motor into each kilogram of material being processed. This is calculated in two steps: 

kw (applied) = kw (motor rating)  × % torque  × rpm running/max. rpm x 0.97 (gearbox efficiency)  

Articles

The author describes the benefits, processes, and practicality of using hot-melt extrusion to mix active pharmaceutical ingredients with pharmaceutical-grade polymers.