Pellets are increasingly being used as multiple unit-dosage forms. They offer manufacturing advantages such as improved flow, reduced friability, narrow particle size distribution, ease of coating and uniform packing, but they also offer therapeutic benefits. For instance, they prevent the buildup of high local concentrations of bioactive agents that might irritate the stomach. They also reduce the variability of plasma profiles between subjects and within the same patient, by reducing variations in gastric emptying rates and overall transit times.
Pharmaceutical pellets are typically manufactured via extrusion spheronization, a three-step process introduced in the late 1960s, that results in spherical granulates roughly 1 mm in diameter. In this process, the powder is formed into a wet mass, which is forced through a restricted area (extrusion) to form strands of extrudate that are broken into short lengths and rounded by placement on a rotating plate within a cylinder.
The resulting spherical granules or pellets are of uniform shape, size and density. When dry, the spheroids have an extremely low friability and are ideally suited for film coating.
Extrusion spheronization’s major advantage over other methods of producing drug-loaded spheres or pellets is its ability to incorporate high levels of active components without producing an excessively large particle.
The process requires at least five unit operations, with an optional sixth screening step. Figure 1 shows each of the process steps along with the critical variables associated with them.
Figure 1. Process flow chart of the extrusion spheronization process, showing the process variables for each individual step.
The end product from each of the steps is shown in Figure 2.
Figure 2. Product produced by the first four extrusion spheronization process steps: (a) powder from dry mixing, (b) granules from granulation, (c) extrudate from extrusion, and (d) spheres from spheronization.
During the first step, powders are dry-mixed to achieve a uniform dispersion before wet granulation. It is generally carried out in the same mixer used for the granulation; however, if a continuous granulator is used, a separate mixer is required for the dry mix. The second step is granulation, during which a wet mass, having the requisite plasticity or deformation characteristics, is prepared. Granulation can be done by batch-type processors (which include planetary mixers, vertical or horizontal high-shear mixers), sigma-blade mixers or continuous mixers (which include the Nica M6 instant mixer6 and high-shear twin-screw mixer-extruders7).
The major difference in this process granulation step is that the amount of fluid needed to achieve spheres of uniform size and sphericity is likely to be greater than that for a similar granulation intended for tableting. This is important to achieving uniform fluid dispersion.
Extrusion is the third step of the process; it consists of shaping the wet mass into long rods, commonly termed ‘extrudate.’ The extrusion process is currently used as an alternative method for the manufacture of completely water-soluble tablets. Extruders come in many varieties, but can generally be divided into three classes.
Screw Feed Extruders
The primary difference between types of screw extruders is in the extrusion zone. An axial or dome extruder transports and extrudes the wet mass in the same plane. Various types of screw-feed extruders are listed below.
- Axial extruders force the wet mass through a flat, perforated end-plate, prepared by drilling holes in a plate.
- Dome extruders use a dome or half-sphere-shaped screen as the die.
- Radial extruders transport material into the extrusion zone where tapered extrusion blades wipe material through a perforated screen.
Gravity Feed Extruders
Gravity-feed extruders include cylinder, gear and radial types. The cylinder and gear types both belong to a broader class, referred to as roll extruders. Both use two rollers to exert force on the wet mass and form an extrudate.
- Cylinder extruders have rollers in the form of cylinders: one solid and one hollow, with drilled holes to form the dies. The wet mass is fed by gravity into the nip area between the two cylinders and forced through the dies into the hollow of the cylinder.
- Gear-type extruders have rollers in the form of hollow gears. The dies are holes drilled at the base of each tooth. Wet mass is forced through the holes and collected in the hollow of the gears as the teeth and the base areas mesh.
- Radial extruders involve rotation of one or more arms to stir the wet mass as it is fed by gravity. Rotating blades wipe the mass against the screen, creating localized forces sufficient to extrude at the nip.
Ram extruders consist of a chrome-plated barrel positioned in a thermostatically controlled storage tunnel. A range of dies can be fitted to the extruder head. Material is loaded into the barrel manually or mechanically and vacuum is applied to eliminate air from the system. The material is extruded through a hydraulically powered ram, with the hydraulic fluid (oil) being passed through a special valve system to sense changes in the plasticity of the material and compensate ram pressure to achieve an even extrusion through the hole.
The working parts consist of a bowl having fixed sidewalls, with a rapidly rotating bottom plate or disk. The rounding of the extrudate into spheres is dependent on frictional forces. Accordingly, the disk is generally machined to have a grooved surface, which increases the forces generated as particles move across its surface. Disks having two geometric patterns are produced: a cross-hatched pattern, with the grooves running at right angles to one another, and a radial pattern, with the grooves running outward from the center. Some studies have shown the rate of spheronization to be faster with the radial pattern; however, either plate will result in an acceptable product.