Multiparticulate oral dosage forms have gained considerable popularity since their market introduction because of their numerous pharmaceutical and technological advantages and their suitability for pediatric use (1–3). From a pharmaceutical point of view, pellets can reduce the variations in gastric drug levels, reduce inter- and intraindividual variations, minimize side effects and high local concentrations, and allow modified-release kinetics. They also enable otherwise incompatible active ingredients to be combined in one dosage form. In pediatrics, pellets offer the advantages of administration with food and the possibility of adjusting doses according to the child's body mass. The major technological advantage of pellets is their capacity to be adapted to successful coating operations (e.g., for a sustainedrelease diltiazem formulation). Furthermore, pellets enhance flow properties during capsule filling, provide a narrow size distribution of particles, and offer low friability.
Among the different methods to produce pellets, the process of extrusion–spheronization is of particular interest (1, 3). Extrusion–spheronization is a semicontinuous process organized in five unit operations: blending, wet granulation, extrusion, spheronization, and drying (4). This process, fast and robust, limits the use of organic solvent and enables drug loading as high as 90%, depending on the active properties, in the mixture. When used to make finished products, extrusion–spheronization produces well-densified pellets, offers a narrow particle-size distribution, yields low friability, ensures regular sphericity, and maintains good flow properties.
The properties of the final product depend on the physicochemical properties of the raw materials and the amount of each component in the formulation (5). Various process variables also affect the quality of the pellets. These variables include the type and quantity of solvent added to the powder mixture; mixing time and speed; type of extruder, design of the screen, and rate of extrusion; spheronization speed, time, load, and plate design; and drying rate and time (2–4).Because various extruder designs are available to prepare extrudates from the wet mass, numerous authors have studied the effect of different extruders on process characteristics and pellet properties. Extruders can be divided into three main categories, according to their feed mechanism: screwfeed (i.e., single- or twin-screw), gravity-feed (i.e., sieve, gear, cylinder, and basket), and ram extruders (3, 4).
Few studies compared any extruders with the ram extruder to provide rheological information and to validate the latter extruder's prediction power. Some authors drew parallels between a ram extruder and a gear extruder or a cylinder extruder, in terms of extrusion characteristics and pellet properties (6–8). Others compared a twin-screw extruder with a gear extruder or with a rotaring-die press by examining the extrusion process and pellet quality (9, 10). A roll-press cylinder also was compared with a basket and a single-screw extruder in terms of pellet characteristics (11). Differences in process and pellet properties between a cylinder, an axial single-screw, a radial basket screen, and a ram extruder were studied (12, 13). The authors underlined great differences between the feeding systems, thus demonstrating that it was not always possible to transfer a formulation directly from one type of extruder to another.
Few authors have compared various extrusion systems with the same extrusion-feed mechanism. This approach seems to be particularly attractive for screw-feed extruders, which can be classified in three categories according to the design of the screen (i.e., axial, dome, and radial) (3). The comparative influence of radial and axial single-screw extruders on the extrusion process characteristics and on the quality of final product was studied using various formulations (14–16). Other authors compared two twin-screw axial extruders for continuous granulation on pellet quality (17). Nevertheless, no author has compared dome technology to the two other screw-feeding technologies. Few authors have studied the dome extruder as a simple tool for extrusion (18–21).
Numerous authors showed the influence of water quantity on extrudate or pellet properties when using a ram extruder, a gravity-feed extruder, a single-screw extruder, or a twin-screw extruder (5, 9, 11, 22–33). Other authors showed that extrusion speed influenced extrudate or pellet quality in ram extruders, gravity-feed extruders, single-screw extruders, and twin-screw extruders (27, 31, 33–37). Several authors showed extrusion systems' different sensitivities to water content and to extrusion speed (10–14, 17).
In this context, studying the influence of water quantity and extrusion speed is an interesting way to highlight differences between extrusion systems. The authors aimed to compare the three systems of single-screw extrusion—radial, dome, and axial—in terms of productivity and the properties of pellets created by extrusion–spheronization. To highlight differences between the three extrusion systems, various levels of water content and extrusion speeds were tested. A majority of previous studies indicated that these two parameters have great influence. The authors set up a response surface design of experiments to reveal the variables' influence and to identify the type of extruder that yielded the best productivity and pellet quality.