Continuous Mixing of Solid Dosage Forms via Hot-Melt Extrusion

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.

Extrusion machinery and design

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 CFR 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.

Twin-screw extruder types

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. 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.)

LSLF twin-screw extruders. 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 rate. 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.

The following formula is relevant:

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

in which D is the screw diameter, n is the screw speed in rpm, and h 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^-1

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.

Shear stress. 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:

Shear stress = Viscosity (E_c) × Shear rate

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_c is preferred if distributive mixing is the goal.

Specific energy. 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:

Applied power:

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

Now we can calculate the SE:

in which SE is denoted in kw per kg/h, kw is kilowatts (the motor rating, kw = hp x 0.746); % torque is the percentage used of the maximum allowable torque; and rpm is the screws' rotations per minute. A lower SE indicates that less mechanical energy is being used, and a larger SE indicates more energy. SE records are particularly important to confirm batch-to-batch consistency, as well as for troubleshooting and scale-up purposes.

Scale-up.Scale-up is useful for estimating rates for production twin-screw extruders based on lab experiments. When comparing different size extruders, the geometries should be nearly identical for this equation to be valid. For processes that scale-up volumetrically, the equation is as follows:

Scale up – Power based: Q_target = Q_reference × [(OD_target)/OD_reference)]³

in which Q is the throughput rate (in any units) and OD is the screw outside diameter (each). The greater the difference in OD, the less reliable this calculation becomes. Accuracy is also dependent upon whether the process is restricted by a volume, heat transfer, or mass transfer limitation. For a heat-transfer limited process, the exponent is closer to 2.0. For mass-transfer limited processes, the scale-up exponent is typically between 2.3 and 2.7 (as compared to 3.0).

For rough scaling between different-size machines that share geometric similarities (OD/ID ratio and similar screw designs) the comparative free volumes are a useful benchmark. For instance:

Q_target = Q_reference × (Volume_target/Volume_reference)

For example, assuming geometric similarities, if an 18 mm twin-screw extruder has a SV of 3 cc/dia and is running at 2 kg/h, then it can be inferred that a 30 mm extruder with a specific volume (SV) of 12 cc/dia will process approximately four times the rate, or 8 kg/h.

Residence time. This formula provides the approximate residence time (RT) in the process section of an HSEI twin-screw extruder. As denoted above, the residence time distribution is highly dependent upon the degree of screw fill. The following equation can be used for RT:

RT(s) = (SV × SG × L/D × %fill)/(Q × 0.2777)

where RT is residence time in seconds, SV is specific volume in cc/dia, SG is specific gravity, L/D is the L/D extruder ratio, % fill is the degree of fill expressed as a decimal (i.e., 40% = 0.4), and Q is the kg/h being processed. The RT formula provides insight as to how long materials are exposed to heat and shear in the process section.

Temperature rise during pressure generation. Pressure generation in the front end of the extruder caused by the die restriction results in a temperature rise. The more restrictive the front end, the higher the pressure and melt temperature rise, which may adversely effect the product. The temperature rise equation is as follows:

Δ T (°C) = Δ P (bar) / 2

in which Δ T is the change in temperature in °C, and Δ P is the change in pressure (1 bar = 14.503 psi). In addition, the extruder rpm and the geometry of the discharge screw elements can drive the melt temperature even higher.

Feeding systems

Feeders set the throughput rate to the twin-screw extrusion system. The extruder-screw rpm is independent from the feed rate and is used to optimize compounding and devolatilization efficiencies. Feedstocks can be pellets, granules, fibers, powders, and/or liquids. Delivery mechanisms include vibratory trays, belts, single screw, and twin-screws for solids; and piston or gear pumps for liquids. As previously stated, the pressure gradient in the process section of the twin-screw extruder is zero for much of the process, which allows downstream unit operations to be performed.

Loss-in-weight feeders measure the flow rate for the feeder via a precision load cell (see Figure 9). As the feeder discharges material to the extruder, the speed of the delivery mechanism adjusts to maintain the desired feed-rate set point. For loss-in-weight controls to work properly, the feeder must be optimized mechanically with regard to the hopper, auger mechanism, and mounting/interface hardware with the extruder. Multiple feeders facilitate introducing ingredients at different positions along the length of the process section. Material handling and refill systems that integrate the appropriate degree of isolation and containment are integrated into the system design.

Figure 9 (All figures are courtesy of the author.)

The feed rate, in combination with the screws' rpm, is integral to the mixing intensity that the materials experience during the HME process. A high feed rate with a low screws rpm will result in a gentle mixing effect as compared with a low feed rate and high screws rpm. Because the feed rate is independent from the screws rpm, the HSEI twin-screw extruder has a wide operating window.

Downstream operations

A wide variety of downstream systems are available after the extruder. Pellets or shapes may be extruded and wound, or cut to length. Film and lamination systems are used to combine melt extrusion with substrates for transdermal applications.

For any HME process, the melt stream must be converted from the circular shape into the final product. The basic die design needs to account for varying material paths and residence times within the die based upon the extrudate dimensions and materials being processed (see Figure 10). Advanced dies would also have some sort of adjustment to maintain a dimensionally stable product. A variety of end products can be produced via hot-melt extrusion.

Figure 10 (All figures are courtesy of the author.)

Pelletization is a downstream process for hot-melt extrusion where the melt stream is pumped through the die, cooled and formed into a pellet, typically between 0.5 and 5 mm. In strand pelletization, "spaghetti" strands are extruded and cooled on a stainless steel or FDA-approved plastic-belt conveyer. The feedrolls of the pelletizer pull the strands and push them into the cutting assembly where cylindrical pellets are produced. Die-face pelletization is also common, where the pellets are cut at the die face and conveyed/cooled by various methods, including chilled air chimneys and vibratory towers. Because many pharmaceutical formulations tend to smear at the die face, this method should be tested prior to implementation. Smaller pellets can be used for direct capsule-filling, and in-line spheronization is also possible (see Figure 11).

Figure 11 (All figures are courtesy of the author.)

For the production of flat film or sheets such as those used in transdermal or dissolvable-film applications, the process melt material is distributed in the die and cooled on rolls. The roll surface is maintained at the desired temperature by pumping a liquid (typically water or oil) through internal cooling channels. The molten material solidifies onto the roll as it cools. Take-off units are available in several different roll-stack configurations such as vertical and/or horizontal arrangements. For many flat products, the nip force across the roll face is used to "squeeze" the extrudate between the rolls. Unwind stations can be used to laminate the film onto a substrate. The final product is then either wound or cut to length.

Shape extrusion occurs when the process melt is directly extruded into a part with specific dimensions. The extrudate can be a simple rod, or complex shape, referred to as a "profile." The extruded profile is formed in the die, sized by calibration tooling, and then conveyed and supported on a conveyer with auxiliary air cooling devices. A belt puller then feeds the product to an on-demand or flywheel-type cutter. In this manner, for example, a 3 mm-diameter by 1 mm-length tablet might be produced.

Summary

Twin-screw extruders are becoming the manufacturing methodology of choice to continuously mix APIs with pharmaceutical grade polymers. Twin-screw extruders are highly flexible and efficient mixing devices suited for producing wide ranging pharmaceutical products that demand consistency and high quality. Understanding the extrusion process, as well as integration of the machine system, is necessary to ensure content uniformity for both compounds produced via hot-melt extrusion.

Charlie Martin is a general manager at Leistritz North America, tel. 908.685.2333, ext 616, cmartin@alec-usa.com

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Additional reading

1. I. Ghebre-Sellassie and C.E. Martin, Eds., Pharmaceutical Extrusion Technology (Marcel-Dekker, New York, 2003).

2. D.B. Todd, Ed., Plastics Compounding Equipment and Processing (Hanser, New York, 1998).

3. J. Wagner and J. Vlachopolous, Eds., The SPE Guide on Extrusion Technology and Troubleshooting (Society of Plastics Engineers, Brookfield, CT, 2001).

4. S. Nowak, "Feeders in Milling and Micronization of Pharmaceutical Powders," Chem.Info (Advantage Business Media, Aug. 2006), available at www.chem.info accessed June 11, 2008.

5. M.M. Crowley et al., Eds., Drug Development and Industrial Pharmacy (Informa Healthcare, USA, 2007).