Materials and methods
Raw materials.
Pellets were prepared from a binary mixture of a drug substance (DS) and microcrystalline cellulose (MCC). The DS, an antidepressant
supplied by Pierre Fabre Research Institute, is highly soluble in water (1250 g/L, median drug particle size: 14 μm, dispersion:
1.5). MCC (Avicel PH101, median drug particle size: 50 μm, FMC Biopolymer, Philadelphia) is insoluble in water. The ratio
of DS to MCC was 36:64 (% w/w) in this study. Purified water was used at different concentrations as liquid binder.
Figure 1: Factors and responses of the experimental design.
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Experimental design.
A response surface design of experiments was built with Design Expert software version 7.0.0 (Stat-Ease, Minneapolis). The
mathematical model targeted for each response studied was a quadratic model with firstorder interactions. The authors studied
three factors: percent water quantity (A), extrusion speed (B), and extrusion system (C). To analyze the results, the extruder
system was included as a qualitative factor, whereas water quantity and extrusion speed were continuous factors.
Figure 2: Pellet-manufacturing flow chart.
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The levels of the continuous factors were determined by preliminary trials. Five levels of water quantity were tested in the
range of 22.5–32.5%. According to preliminary tests, it was impossible to create pellets with water quantities beyond these
limits. Three levels of extrusion speed were tested in the range of 20–60 rpm. Radial, dome, and axial extrusion systems were
tested. All other experimental conditions were kept constant. Two replicates of the median conditions (i.e., 27.5% water and
40 rpm extrusion speed) were run for each extruder type. The experimental design comprised 27 experiments. All factor-level
combinations were carried out in a randomized order. Figure 1 summarizes factors and responses selected for the design of
experiments.
Figure 3: Extrusion of the wet mass in radial, dome, and axial extrusion systems.
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Pellet preparation.
MCC pellets containing 36% DS were made by extrusion–spheronization. Dry blending of MCC and DS was a common step to all the
batches. After blending, 550 g of dry mix were sampled for subsequent steps. Wetting and granulation were performed in an
Aoustin kneader (RPA Process, Nanterre, France). The wet mass obtained was extruded in an MG-55 extruder (FujiPaudal, Osaka).
The extrudates were then spheronized in a Multi Bowl Spheronizer 250 (Caleva, Sturminster Newton, UK) and the pellets obtained
were dried in a UT6120 drying oven (Heraeus, Hanau, Germany). Process conditions were fixed according to the flow chart shown
in Figure 2. The authors used the MG-55 single-screw extruder to test the three extrusion configurations (see Figure 3). The
axial system incorporated a flat end-plate screen perpendicular to the end of the screw. The dome system had an arch-shaped
endplate screen at the end of the screw. The extrudates were ejected out of the screens at the end of the axial and dome extruders.
In the radial system, the screen was placed around the screw so that the extrudates were ejected perpendicular to the motion
of the screw. A die of 2 mm in diameter was used in this study to allow comparisons. The extruders' total open areas also
were different. The screen thickness of the radial, dome, and axial systems presented 52.4, 22.7, and 15.5% open area and
a 1-, 1.2-, and 2-mm screen thickness, respectively.
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