Extrusion-Spheronization Process Variables and Characterization

Critical Reviews in Therapeutic Drug Carrier Systems, 26(3), 275331 (2009)
Extrusion-Spheronization: Process Variables and Characterization

V. R. Sinha,* M. K. Agrawal, A. Agarwal, G. Singh, & D. Ghai
Division of Pharmaceutics, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India
*Address all correspondence to V.R. Sinha, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India; sinha_vr@rediffmail.com
ABSTRACT: Multiparticulate systems have undergone great development in the past decade fueled by the better understanding of their multiple roles as a suitable delivery system. With the passage of time, significant advances have been made in the process of pelletization due to the incorporation of specialized techniques for their development. Extrusion-spheronization seems to be the most promising process for the optimum delivery of many potent drugs having high systemic toxicity. It also offers immense pharmaceutical applicability due to the benefits of high loading capacity of active ingredient(s), narrow size distribution, and cost-effectiveness. On application of a specific coat, these systems can also aid in site-specific delivery, thereby enhancing the bioavailability of many drugs. The current review focuses on the process of extrusion-spheronization and the operational (extruder types, screen pressure, screw speed, temperature, moisture content, spheronization load, speed and time) and formulation (excipients and drugs) variables, which may affect the quality of the final pellets. Various methods for the evaluation of the quality of the pellets with regard to the size distribution, shape, friability, granule strength, density, porosity, flow properties, and surface texture are discussed. Key WoRdS: extrusion, spheronization, operational variables, formulation variables, evaluation
I. INTRODUCTION
The pellets or beads produced by the extrusion-spheronization process offer several advantages over conventional drug delivery systems. For example, this process produces spheroids with high loading capacity of active ingredient(s) without producing extensively large particles. It also produces particles of uniform size with narrow size distribution and good flow properties. Successful coating is applied to the spheroid because of its spherical shape and low surface areato-volume ratio. Pellets composed of different drugs can be blended and formulated in a single-unit dosage form that facilitates the delivery of two or more chemically compatible or incompatible drugs at the same or different sites in the gastrointestinal (GI) tract. As a
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drug delivery system, pellets offer therapeutic advantages such as less irritation of the GI tract and a lowered risk of side effects due to dose dumping.1 Pellets are frequently used in controlled- release delivery systems because they facilitate free dispersion of spheroids in the GI tract and offer flexibility for further modification.2 Pellets with a mean diameter ranging from 500 to 1500 m are generally used in the pharmaceutical industry.3 Pelletization is referred to as an agglomeration process that converts fine powders or granules of bulk drugs or excipients into small, free-flowing, spherical, or semi-spherical units, referred to as pellets.3 In the extrusion-spheronization process, pellets are prepared from mixtures of solids and liquids with the involvement of forming and shaping forces.4 This procedure had great practical significance because it enhanced the status of pellets in pharmaceutical drug-dosage form development. The direct pharmaceutical applications of the process for the development of pellets were first published in the literature in the early 1970s.58 The process is capable of producing pellets containing more than 90% active ingredients, provided that the physicochemical properties of the drug and other formulation constituents are optimum.3 The process has been the subject of intensive research ever since and has gained immense popularity. Pellets possess many physiological advantages; for example, they disperse freely in the GI tract, maximize drug absorption, reduce peak plasma fluctuations, and minimize potential side effects and toxicity owing to the reduction in dose and increased bioavailability.9,10 Pellets also tend to avoid high local concentrations of bioactive agents, which may inherently be irritating or anesthetic to the stomach.11 Additionally, pellets reduce intra- and intersubject variability of plasma profiles by reducing variations in gastric emptying rates and overall transit times. Extrusion and spheronization involves four main steps (Fig. 1): preparation of the wet mass (granulation), shaping the wet mass into cylinders (extrusion), breaking up the extrudate and rounding of the particles into spheres (spheronization), and finally drying of the pellets. Because these phases are interrelated, the quality of the end product is also strongly dependent on the process.6,12 Spheronization has been evaluated as a specialized wet-granulation process. Researchers have studied and compared the sphericity properties of pellets and granules prepared by extrusion-spheronization, conventional wet granulations,7 and the pan method.13
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FIGURE 1. Processing flow chart indicating the individual processing variables in the spheronization process using an extruder and a spheronizer.
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Extrusion and spheronization has also gained increased usage as a potential technique and as a method of choice for the preparation of multiparticulate controlled release (CR) dosage forms. The advantages of using small spherical pellets or beads in oral controlled drug delivery are well documented.2 Their use improves the safety and efficiency of active ingredient, and helps to increase bioavailability of drugs by controlling or modifying their release rate. The spherical granules or pellets produced by the extrusion-spheronization technique feature a regular shape with uniformity in size and density. When dry, the spheroids have an extremely low friability and are ideally suited for film coating. Pellets can be layered with the drug and coated with various polymers to control the release rate. Furthermore, different types of pellets with different release rates can be combined in a simple capsule to provide the desired CR profile. The CR formulations prepared by extrusion-spheronization are mainly divided into two categories: coated pellets and matrix pellets.2 Pellets prepared by the extrusion-spheronization process have also been studied with respect to several formulation and process variables. The pellet properties can be affected by many operational variables during the extrusion, spheronization, or drying stage. The various variables, which affect the final pellet qualities, are screen hole diameter,14 screen pressure,15 extruder type and speed,16 type of friction plate,1719 extrusion temperature16,20 and spheronization time,21 and speed and load.22 The current review outlines the general concepts of pellet preparation by the extrusion-spheronization method and assesses the influence of various operational and formulation variables on the properties of the so-formed pellets. The evaluation parameters of pellets prepared by extrusion-spheronization are also discussed.
II. EXTRUSION
The extrusion operation is an integral part of the overall spheronization process in which the wet powder mass is forced through a restricted cross-section. The dimensions of the restriction in terms of radius and length differ from system to system. A diameter of less than 500 m is not often encountered.4 Nevertheless, some researchers have used an extruder screen of 400 m in diameter to obtain pellets of this size range.14 Extruders of different sizes can be used depending on the load they can handle. The instrumentation of the extruders also varies, which may affect the quality of the extrudates.
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II.A. Extruder Types

Researchers have used different types of extruders to control the extrudate, and subsequently the final pellet properties. These include: a) screw extruders (axial and radial type), b) sieve extruders, c) basket extruders, d) roll extruders (roll extruder with one perforated roll, roll extruder with two perforated rolls, roll extruder with the extrusion screen rotating around the rollers), and e) ram extruders.23 Table 1 describes the types of extruders and their characteristics. The screw extruder consists of either one or two Archimedes screws, also called a twin screw in the case of two. These screws feed the plastic mass to the axial or to the radial extrusion screen.
TABLE 1. Types of Extruders and Their Features

Type of extruder 1. Screw extruders Axial type Radial type Features Consists of one or two screws feeding the plastic mass to an axial or radial extrusion screen Screen is placed at the end of the screw, perpendicularly with the axis of screw Die is placed around the screw, discharging the extrudate perpendicular to the axis of the screw The granulate is fed by a screw into the extrusion chamber, where a rotating or oscillating device pushes the plastic mass through the screen. Here the screen is positioned at the bottom of the extrusion chamber Similar to sieve extruder, the difference being that the granulate is fed by gravity into the extrusion chamber and that the vertical walls of the chamber make up the extrusion screen Contains two contra-rotating wheels, of which one is perforated Both the contra-rotating wheels are perforated Contains a perforated cylinder rotating around the rollers, which rotates around one or more rollers, discharging the material to the outside of the cylinder Based on a piston, which pushes the wet mass through the screen situated at the end of the barrel
2. Sieve extruder
3. Basket extruder
4. Roll extruders With one perforated roll With two perforated rolls With the extrusion screen rotating around the rollers
5. Ram extruder
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FIGURE 2.
Schematic view of an axial type screw extruder.
In the axial type of screw extruder, the screen is placed at the end of the screw, perpendicular with the axis of the screw (Fig. 2). In the radial type of screw extruder, the die is placed around the screw, which discharges the extrudate perpendicular to the axis of the screw (Fig. 3).23,24 In sieve and basket extruders, the granulate is fed by gravity or by a screw into the extrusion chamber, where an oscillating or rotating device pushes the plastic mass through the screen.23 The screen is positioned at the bottom of the extrusion chamber in the case of a sieve extruder (Fig. 4). In a basket extruder, the vertical walls of the extrusion chamber make up the extrusion screen. There are two types of roll extruders. The first is an extruder equipped with two contra-rotating wheels, one or both of which can be perforated. In the first type of extruder, the mass is fed between
FIGURE 3.
Schematic view of a radial type screw extruder.
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FIGURE 4. Schematic view of a sieve extruder.
the two wheels and the extrudates are collected inside the extrusion wheels. The second type of roll extruder has a perforated cylinder that rotates around one or more rollers. These rollers helps to discharge the material outside the cylinder (Fig. 5).23 With the second type of extruder, it is possible to measure the forces during extrusion through the two perforated cylinders, which can then be correlated to the final quality of the pellets.25
FIGURE 5. Schematic view of a roll extruder with: (A) a single perforated roll, (B) two perforated rolls, and (C) a set of rollers rotating inside a perforated extrusion screen.
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FIGURE 6.
Schematic view of a ram extruder.
Finally, the ram extruder consists of a piston that pushes the wet mass through the screen situated at the end of the barrel (Fig. 6). The force necessary to maintain the set extrusion speed can be measured.19,26
II.B. Extrusion Operational Variables

Various variables of extrusion operation that have significant effects on the extrudate, and thus the final pellet qualities, are: 1) screen pressure, 2) screen hole diameter, 3) extruder type, 4) screw speed, and 5) extrusion temperature. 1. Screen Pressure In the process of extrusion, stress is necessary to force a wet mass through small orifices. The quantitative estimation of the screen pressure upon extrudability has been studied by various researchers.15,2731 In 1994, Shah et al. measured the screen pressure by tangentially mounting a strain gauge load cell.30 Screen pressure was found to be linearly related to the amount of water used for granulation. In addition, the maximal yield of 18/25-mesh cut pellets was uniquely related to the screen pressure. In a 1995 Box-Behnken experimental design study, Shah et al. concluded that screen pressure was the most critical variable affecting the yield of 18/25 mesh cut pellets.31 Baert et al., who processed a series of microcrystalline cellulose (MCC)-dicalcium phosphate formulations, have described the instrumentation of a pilotscale gravity-feed extruder.25 A decrease in extrusion force was observed with increasing water content. For a constant MCC/water ratio (50:50), the addition of lactose or dicalcium phosphate resulted in differing profiles, often with a minimum force at a certain level of filler.
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Boutell et al. investigated the effect of glycerol and surfactant (sodium lauryl sulfate and Pluronic F68) solutions on the extrusion force of MCC and barium sulfate.15 Glycerol solution tended to increase the extrusion force, whereas surfactant solutions decreased it. Due to changes in the extrusion force, the water content in the extrudate also differed and there was a wider size distribution of the pellets. Tomer et al., however, could not find a relationship between the extrusion forces required to extrudate the wet mass and the size of the pellets.27 For the same extrusion force, it was possible to obtain different performances, when different combinations of the ingredients with a single drug were used or when different drugs were used. Thus, the authors concluded that there are some other factors that affect the size of pellets, the spheronization process, and so forth. Thus, the simple extrusion force measurements were insufficient to characterize the ability of the extrudate to spheronize. Kleinebudde reported that the power consumption-controlled extruder is an appropriate tool to adjust the extrusion force.32 For this purpose, it is necessary to run the extruder at a specific level of power consumption. Kleinebudde extruded the binary mixtures of MCC and dicalcium phosphate dihydrate by a power consumptioncontrolled extruder and evaluated the water content of the extrudate for the production of spherical pellets.32 The author also reported the influence of screw speed and powder feed rate on the required level of power consumption. The screw speed did not have significant effects on the water content, and consequently the shape of the pellets, in the range studied. Conversely, variations of the powder feed rate affected both the water content and the shape of the pellets. In a subsequent study, Kleinebudde et al. observed the power consumptioncontrolled extruder and investigated the influence of the degree of polymerization (DP) of cellulose materials on the behavior of these materials during homogenization and the extrusion-spheronization process.33 The authors concluded that during the extrusion process, water content in the extrudate and pellet porosity were increased as the DP was increased for the extrudates produced at the same level of power consumption. Kanbe et al. reported on the feasibility of the manufacture of fine spherical granules by the extrusion-spheronization method.34 A screen with a pore size of 0.4 mm or smaller was used for extrusion, and a reduction of the extrusion pressure at the screen was necessary to prevent the screen from breaking. In light of the reduction of the screen pressure, the authors found that the low substituted
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hydroxypropyl cellulose (L-HPC), croscarmellose sodium (Ac-Di-Sol), and carmellose calcium (ECG-505) markedly decreased the screen pressure. The high swelling property of these excipients was closely related to screen pressure reduction.34 Thus, screen pressure is directly dependent upon the amount of load, amount of water used for granulation, composition of blend, and a few operational parameters such as the pore size of the screen and screw speed. A slight change in these parameters changes the screen pressure and thus the extrusion force, and the variation in extrusion force affects the yield and size distribution of pellets. 2. Screen Hole Diameter Pellet quality is dependent on the extrusion screen, which is characterized by two parameters: the thickness of the screen and the diameter of the perforations. The dimension of the screen holes during extrusion is an important parameter that affects the final pellet properties, especially the mean pellet diameter.3537 Baert et al. reported on the difference in extrudate quality by extrusion with different screen thicknesses.17 The authors found that the screen with low thickness formed a rough and loosely bound extrudate, whereas the screen with high thickness formed a smooth and well-bound extrudate because of the higher densification of the wet mass in the screen with the greatest thickness. Similarly, the diameter of the perforations determines the size of the pellets, with a larger diameter in the perforations producing pellets with a larger diameter when processed under the same conditions.18,19 An increase in the extruder screen opening size was found to result in an increase in the hardness of the tablets made from these pellets.38 Dupont et al. used an extrusion screen with orifices of 400 m in diameter and selected a formula that would pass through the small holes of the screen during extrusion.14 Shah et al. reported the effect of screen aperture size on screen pressure exerted and their research indicated that the percentage open area of the screen determined the rank order of screen pressure, not the screen aperture size.31 Gomez-Carracedo et al.39 and Bianchini and Vecchio40 have also studied the effect of extruder screen opening on the final pellet properties. The diameter of the perforations and thickness of the screen are the two major parameters that alter the screen pressure and affect final pellet properties such as size, surface morphology, shape, and
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hardness. The selection of optimal screen size further depends upon the specific size requirements of the pellets based upon their application. 3. Extruder Type As described earlier, many types of extruders have been used for the process of extrusionspheronization. Accordingly, the type of extruder influences the extrudate quality and, consequently, the pellet qualities. Screen-type extruders induce minimum force.4 Kleinebudde and Lindner described the instrumentation of a twin-screw axial screenmixer extruder.16 Due to an increase in the die length, the forces of extrusion were considerably larger than those of the radial screen extruders. Forces of 1 to 5 bar were recorded, depending on screw speed or, more significantly, the water content. Different types of extruders result in pellets exhibiting different characteristics. Thoma et al.41 used four different types of extruders, , all of which required different amounts of water in their formulations; sphericity and mean pellet size also differed significantly among the extruders. The Alexanderwerk gravity-feed roll extruder and NICA radial-screw extruder showed a linear dependence of the mean pellet size on the water content of the formulations, whereas the Gabler axial single-screw extruder showed an almost unchanged pellet size over a wide range of water contents, which proved that the formulation could not be extruded successfully in the latter. Batches that were extruded on the NICA unit showed a significantly lower bulk density than the Alexanderwerk or Gabler batches. The NICA batches also exhibited a significant difference of the Hausner factor from the other two extruders. Thoma and Ziegler evaluated the difference in extrudate properties by using the different types of extruders mentioned above.42 Unlike the others, the Gabler extruder failed to extrudate formulations containing more than 60% soluble ingredients such as lactose or mannitol. The increase in surface smoothness of the extrudate with increase in water content of the formulations also differed in the Gabler unit. The selection of the extruder is critical because they are not interchangeable.4 In addition, not all of the extruders are designed solely for pharmaceutical use, and some food-grade extruders might not meet the Good Manufacturing Practices requirements. In some formulations, only a change in the water content is required when the
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extruder type is changed. For example, the ram extruder required a 2% difference in water content compared with a gravity-fed cylinder extruder when preparing spheres of equivalent size and shape.43 Baert et al. found that although a small basket extruder would certainly be appropriate in combination with a paudal screen extruder, it would probably not be for an axial screw or gravity-fed extruder. In this case, the ram extruder would be a closer approximation.17 In conclusion, the composition of the blend and the amount of water required mainly influence the type of the extruder used for obtaining a product with the desired size and sphericity. The choice of extruder type also affects the density and thereby the Hausner ratio of the pellets. 4. Screw Speed Screw speed of the extruder seems to have little effect on the final pellet qualities; it is the powder feed rate to the extruder that affects both the water content and the shape of the pellets.32,44 The total output of the extruder is mainly governed by the extrusion speed. The output should be as high as possible for economical reasons, but several authors18,19,45 state that an increase in the extrusion speed can influence the size and surface properties of the final pellets. Several studies show that the surface impairments, such as roughness and shark skinning, become more pronounced with increasing speed. The surface effects of extrudate lead to pellets of lower quality because the extrudate will break up unevenly during the initial stages of the spheronization process, resulting in a number of fines and a wide particle size distribution. 5. Extrusion Temperature Extrusion temperature influences the pellet quality by affecting the moisture content. The rise in temperature during the extrusion cycle could dramatically alter the moisture content of granules because of evaporation of the granulation liquid. This may lead to a difference in the quality of the extrudate produced at the beginning of the batch and that produced at the end of the batch. Evaporation of water during extrusion is possible because most of the water is available as free water. Extrusion temperature control becomes an important parameter when a formulation with a thermolabile drug is processed. To avoid a rise in temperature during an extrusion cycle, the use of
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a screw extruder with a cooling jacket around the barrel to keep the temperature of the given formulation between predetermined limits has been reported.16,20
III. SPHERONIZATION
The spheronization operation is the single step that differentiates the extrusion-spheronization process from conventional wet granulation and therefore is the term commonly used to describe the overall process.46 The basic design of all the spheronizers obtained from different manufacturers is similar, in that a friction plate is rotated within the confines of a cylinder. The diameter of the plate may range from 10 to 1000 cm depending on the load of the material.4 All spheronizers have a smooth wall as part of their design. The plate design, however, differs and plays a very important role in the final quality of the spheroids.47 Other characteristics, such as the diameter of the plate and its speed, also have been found to show intense effects on the pellet qualities. As early as 1972, Woodruff and Nuessle reported that by increasing the speed of the plate, more uniform and rounder pellets were obtained.6 They found that the pellets exhibited better roundness than the commercial nonpareil seeds and had excellent flow and packing properties. Lovgren and Lundberg observed that speed in combination with the diameter of the plate is important, rather than the absolute speed of the friction plate.48 From these two parameters, the plate peripheral velocity can be calculated, and these data should be compared instead of the absolute rotational speed of the friction plate.48 The surface of the friction plate used for extrusion-spheronization is grooved. Two types of groove geometry exist: cross-hatch geometry, where the groves form right angles, and radial geometry, where the grooves form a radial pattern.24 The edges of the grooves are required to facilitate the critical cutting of extrudates to form shorter and almost uniform-length segments.49 Such grooved plates are the most appropriate for extrusion-spheronization. In the case of drug layering with nonpareil seeds or coating with core spheroids, plates with a smooth surface may be used.38 For rotary processing, in which spheroids can be formed from powders in a single step, frictional plates with tear drop studs are used.4951
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III.A. Mechanism of Spheronization

During the spheronization process, the cylinders obtained from extrusion are dumped onto the friction plate, where the extrudate is broken up into small cylinders with a length equal to their diameter.5 Two mechanisms are proposed for the formation of the shears. According to Rowe, these plastic cylinders are rounded due to frictional forces by going through different stages that can be distinguished depending on the shape of the particles; that is, starting from a cylinder over a cylinder with rounded edges, to dumbbells, to elliptical particles, and eventually to perfect spheres.24 Another mechanism proposed by Baert and colleagues suggested that a twisting of the cylinder occurs after the formation of cylinders with rounded edges, finally resulting in the breaking of the cylinder into two distinct parts, each with a round and a flat side.17 Due to the rotational and frictional forces involved in the spheronization process, the edges of the flat side fold together like a flower, forming the cavity observed in certain pellets. Reitz and Kleinebudde reported that the spheronization of drugcontaining extrudates of Dynasan 114 and Witocan 42/44, on the basis of a binary lipid mixture of hard fat and GTM, is feasible using a spheronizer without the addition of solvents.52 Under suitable process conditions, spherical pellets with low porosity, defined surface area, and narrow particle size distribution with an aspect ratio of below 1.1 and equivalent diameters of approximately 1.5 mm were obtained from 1-mm extrudates. The spheronization process was shown to be strongly temperature and formulation dependent. The material temperature during the process was influenced by the adjusted jacket temperature and friction and shear forces between the rounded particles.
III.B. Spheronization Operational Variables

1. Spheronization Load, Speed, and Time Chapman et al. looked at the optimum pay load required for the preparation of the best-quality, and found that extremely small quantities provided insufficient plate-particle interactions.53 Alvarez et al. illustrated the effects of spheronization load and spheronization rate on mean pellet size and micropore volume using response surface methodology, and concluded that the pellet size and porosity can be controlled by modifying the spheronization rate and spheronization
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load.22 For both Avicel grades (PH 101 and PH 102) used in the study, an increase in the spheronization load at a constant spheronization rate resulted in a decrease in both mean pellet size and micropore volume. The shape was characterized by the circularity parameter as defined by Exner and Link, which was found to increase with an increase in both spheronization rate and load.54 In a factorial experiment, Gouldson and Deasy evaluated the effects of spheronization load and spheronization time on pellet qualities.21 The yields of pellets obtained at a shorter spheronization time of 5 min were larger than those obtained when the extrudates were spheronized for 10 min. There were also a number of significant interactions between these variables. With small spheronization loads, the yield of large pellets increased with longer spheronization times, which was exacerbated by faster spheronization speeds. When larger spheronizer loads were used, the production of large pellets was increased by increasing spheronization time when spheronized at 600 rpm. At 800 rpm, the production of large pellets was high, regardless of spheronization time. With increasing spheronization time, the yield of fines reduced significantly. An increase in spheronizer speed increased the packing density because of the great compaction forces applied. An increase in spheronization speed and spheronization load also resulted in an increase in the sphericity of the pellets. The most spherical pellets were obtained when both factors were held at high levels. Increasing the spheronizer load increased the relative humidity of the spheronizer chamber during spheronization, deterring further evaporation of water from the pellets into the chamber environment. The smaller reduction in the pellet moisture level could be responsible for more spherical pellets.21 The spheronizer plate with the rougher surface applied more mechanical energy to the extrudate and wet pellets, which reduced the water content necessary for the formation of good pellets. The influence of plate geometry on the size and shape of the pellets was studied by Schmidt and Kleinebudde (1998).47 Kleinebudde et al. found that the spheronization speed has an influence on the size but not on the porosity of the pellets.55 Sphericity also increased with an increase in the spheronizer speed.56 When spheronization time was increased, sphericity, surface smoothness, and size of the pellets were increased. Iyer et al. measured the percent yield, tapped density, and sphericity index as a function of spheronization time.29 Maximum yield was achieved within 60 sec in
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the spheronizer. The shape and density were found to be unchanged by increasing the residence time, whereas the yield was severely reduced. Pellet size and shape are highly influenced by the surface roughness of the spheronizer plate. There is considerable interaction between spheronization time and spheronization. Both the mean pellet size and micropore volume change with a change in spheronization rate and spheronization load. Similarly, pellet size, circularity, and yield change with the change in spheronization time and spheronization load. With small spheronization loads, the yield of large pellets increases with longer spheronization time, and this can be exacerbated by faster spheronization speed.
IV. DRYING
At the end of the spheronization process, the wet pellets must be dried4 to complete the formation of the matrix structure.57 The drying step should not be considered as a secondary process; in fact, it could be used as another tool to modify pellet characteristics such as size, density, and hardness.58 Both the drying temperature and the drying method can have profound effects on pellet properties. There appears to be no shape change upon drying but diameter may vary.58 The higher the temperature employed for drying, the smaller the diameter, indicating a shrinking process. The diameter findings are supported by the density determinations, which increase with the increasing temperature. Microwave drying almost suppressed the shrinkage process.58 In this case, drying was faster and uniform, and almost all water content was evaporated in the first few minutes of the process; consequently, the matrix structure remained intact in the majority of the pellets and shrinking reached the smallest value. This pellet property was witnessed in the case of freeze-drying as well.57 Bataille et al. also studied the changes in pellet structure with different drying methods, and found that the porosity and pore diameter as measured by mercury intrusion porosimetry (MIP) were higher when pellets were dried in a microwave oven than when they were dried in a tray dryer.59 Because pellets densify further during the drying phase, the procedure for water removal may be of crucial importance to their microstructural properties.60 Discussion about the incidence of drying on the properties of pellets usually only concern the speed at which the removal of water occursthat is, quickly (microwave-drying or
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freeze-drying) or slowly (oven-drying or desiccation on silica gel).61 Comparative studies on the contraction of cellulosic pellets as a function of the drying technique indicate that the reduction in the volume ranks in the following order: oven > fluidized bed > freeze-drying.57 It has been reported that freeze-dried pellets are more porous and have more pores open toward the surface than those desiccated on silica gel, in which closed pores are predominant.62 The impact of the granule drying technique (oven drying and freeze-drying) on tablet strength and dissolution characteristics was investigated for a range of propyl gallate (PG)/MCC/water granules generated via extrusion-spheronization. The tablet compaction data indicated that the granule yield point was significantly lower for the freeze-dried granular material with increased tablet strength after compaction. As a consequence, for tablets compacted to the same final applied stress, the tablet surface was visibly smoother than that of the oven-dried counterparts. Dissolution profiles were similar for tablets prepared using the oven-dried or the freeze-dried granules obtained by the process of extrusion-spheronization.63 Gomez-Carracedo et al. concluded that the drying procedure caused remarkable differences in pellet size and porosity: freeze-dried pellets were 3-fold more porous than those oven-dried.64 The microstructural, morphological, and mechanical properties can be modulated, to a large extent, through the control of the drying step. In another study done by the same researchers,65 the slowly frozen pellets had the lowest porosity but the pores were larger. Pore size appears to be a critical factor for achieving controlled release; the greater the pore size, the faster the entrance of water and, consequently, the faster the drug release. Therefore, if freeze-drying is used to remove water from wet pellets, the control of the ice formation is essential in modulating the release profiles. MCC, polyvinylphenol (PVP), Eudragit RS PO, and Eudragit RL PO pellets were prepared by extrusion spheronization. The pellets were cured in oven at 60oC for 24 h. It was shown that the cured pellets containing 40% or 60% drug exhibited a plastic deformation without any fracture under mechanical tests (Fig. 7). The curing process resulted in a significant decrease in the elastic modulus of the pellets. The transition of pellet behavior from brittle to plastic upon curing was due to a shift in the Eudragit structure from a glassy to rubbery state, which was supported by differential scanning calorimetry (DSC) studies. The curing process also retarded drug release from pellets and increased mean dissolution time (MDT).66
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FIGURE 7. Scanning electron micrograph of the surface of a pellet containing 60% ibuprofen before curing (A) and after curing (B). Reprinted from the European Journal of Pharmaceutics and Biopharmaceutics, vol. 67/ed. 1, Abbaspour MR, Sadeghi F, and Garekani HA, Thermal treating as a tool to produce plastic pellets based on Eudragit RS PO and RL PO aimed for tableting, pp. 2607, Copyright 2007, with permission from Elsevier.66
Both drying technique and drying temperature have a very profound effect on pellet structure and their properties such as shape and porosity of pellets. Therefore, these factors should be chosen on the basis of composition of blend and the desired drug release from the pellets.
V. INFLUENCE OF MOISTURE ON EXTRUSION-SPHERONIZATION

Pellet preparation by extrusion-spheronization is impossible without the presence of a suitable granulating fluid, which provides appropriate rheological properties to the formulation so that the mass can be extruded through the extrusion screen and transformed into spherical pellets.4 MCC is the most widely used excipient in extrusionspheronization.3,4,67 To spheronize MCC, the presence of water as a granulating fluid is the most important formulation requirement, even in very small quantities.68 In addition, the pellet quality improves on increasing the percentage of water in an ethanol/water mixture.
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Water content of the formulation, both before and after extrusionspheronization, is very important in governing pellet quality, and many studies have focused on this aspect of the process.8,69 Heng and Koo concluded that all of the essential qualities of pellets such as pellet size, flow rate, friability index, bulk, and tapped densities varied with the amount of water used during the process.70 They reported that mean size, as determined by logarithmic geometry, increased linearly with the amount of water added for all of the 11 MCC grades studied. The flow rate decreased with increasing water content, which can be correlated with the increase in pellet size accompanying the increase in water content: larger pellets cannot flow through orifices as easily. Pellets produced using 45% (w/w) water content were too large for flow measurements. Pellets were less friable when the water content was higher. At water contents of 40% (w/w) and above, friability indices of pellets produced from different MCC grades did not differ significantly compared with those produced at lower water contents. The reason for this was ascribed to the formation of a solid bridge upon drying, as higher water content ensured that there was more lactose in the dissolved form (used in the formulation). Water contents of around 3540% (w/w) produced pellets of the highest bulk and tapped densities. Beyond this, an increase in water content produced bigger pellets that packed less well and showed lower densities.
V.A. Evaluation of Rheological Properties of Wet Powder Mass

Many methods have been used to evaluate the rheological properties of wet powder masses (and, indirectly, the water content). These include: 1) capillary rheometry,26,7175 2) mixer torque rheometry,76 3) powder rheometry,77 and 4) controlled stress rheometry.78,79 Plasticity measurement of the drug excipient mixture is another parameter, which can be correlated to the type and amount of granulating liquid used. Elbers et al.80 quantified the plasticity of formulations using an apparatus originally reported by Alleva and Schwartz,81 and characterized their behavior with respect to the type and amount of granulation fluid. It was concluded that the optimum extrusionspheronization conditions could be determined by measuring the plasticity of the drug excipient mixture as a function of the amount of granulation fluid. The variation of water content in the formulation can also occur during both the extrusion and spheronization stages. The water
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movement in the mixture depends on both the formulation and the applied stress. There are two stages of extrusion that can induce water movement: 1) forcing of the mass from a large diameter into the die, and 2) forcing the wet mass along the die.79 During spheronization, the centrifugal force induced by the rotation of the plate can cause water to migrate to the surface, resulting in agglomeration of the pellets.15 There will also be a wider size distribution, as the extrudate will vary in water content. If the moisture content is less than the lower limit, a lot of dust will be formed during spheronization, resulting in a large yield of fines.67,82 Satisfactory extrusion of such dry systems is unlikely, because excessive pressure is required to consolidate the material to remove the air voids. Extrudate is brittle in this low state of saturation and will shatter, generating a large quantity of fines when broken up on spheronization and having insufficient plasticity to form spheres. Agglomeration can occur if the surface of the half-formed pellets bed is too wet during spheronization. If the amount of liquid in the granulation is higher, then the liquid distribution within it is also higher.83 In such cases, due to capillary suction, the liquid from inside will move to the surface, which results in agglomeration. Agglomeration may also occur by coalescence,84 and may be increased by any means, which tends to increase the deformability of moist aggregates (for example, by reducing their tensile strength and/or by improving their plastic deformation).
V.B. Assessment of Water Movement in Extrusion-Spheronization

The assessment of the ease of water movement in a formulation can be useful in assisting formulation development and can be done by various techniques: 1) the pressure membrane technique,15,85 2) subjecting a wet mass to extrusion through a die and evaluating the variation in water content of the extrudate,8688 3) NMR imaging,87,88 and 4) the centrifuge technique.8789 Boutell et al. quantified the volume of liquid movement through a bed of MCC, barium sulfate, and a 1:1 mixture of the two at various applied pressures.15 As the pressure was increased, more water was removed. MCC showed a slow but continuous removal of water compared to the bed of barium sulfate alone. When the two excipients were mixed in equal proportions, the mixture behaved
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more like MCC than barium sulfate. When surfactants were added, there was considerably more water removal from the bed of MCC. The lower the surface tension and the contact angle, the greater the water removal. With an increase in the percentage of barium sulfate in the mixture with MCC, the quantity of water required also increased to produce a consistent product in terms of size.90 As the percentage of barium sulfate increased to 80%, significant moisture content was required. Fielden et al. found that the particle size of lactose in pellets containing MCC and lactose influenced the appropriate amount of moisture content required for successful pelletization,82 and related this effect to the difference in the mobility of water in the different packing structures produced by the different particle sizes of lactose. The water requirement for formulations containing fine lactose particles was relatively wide as compared with those containing coarse lactose particles. At the same moisture content, the extrudate containing coarse lactose appeared to be more plastic than the fine lactose extrudate, because it produced a greater percentage of granules within that size fraction at all time points. Abbaspour et al. have shown that the amount of water required to prepare a proper wet mass is affected by the composition of the formulations.91 The required amount of water decreased with increasing drug load and percent of PVP. These authors also showed that formulations containing Eudragit RL require more water. Prieto et al. characterized the different excipients in terms of morphometry and basic physical properties.92 Torque rheometry was used to characterize the rheology of wetted masses of the different excipients and excipient mixtures, with the aim of determining the optimal amount of wetting agent (water). The authors also evaluated the water absorption and water retention capacities of each excipient. Consistency of equilibrated wet masses (prepared with the predicted optimal amount of wetting agent) was not an effective predictor of extrusion-spheronization efficacy due to methodological differences with respect to the stepwise water-addition assay and to the addition of wetting agent all at once rather than stepwise. Unlike microcrystalline cellulose mixtures (in which the optimal amount of wetting agent for extrusion-spheronization is that giving maximum torque), the optimal amount of wetting agent for the starch and starch-dextrin mixtures tested in this study was lower than that giving maximum torque. In fact, the optimal amount of wetting agent was more accurately predicted by maximum torque amplitude.
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FIGURE 8. Scanning electron micrograph showing the effect of the granulating liquid on the shape, size, and size distribution of alginate pellets. (A) 10% PVP in 5% ethanol and (B) 3% calcium chloride solution. Reprinted from the European Journal of Pharmaceutics and Biopharmaceutics, vol. 67/ed. 1, Sriamornsak P, Nunthanid J, Luangtana-anan M, and Puttipipatkhachorn S, Alginate-based pellets prepared by extrusion/spheronization: A preliminary study on the effect of additive in granulating liquid, pp. 22735, Copyright 2007, with permission from Elsevier.93
Sriamornsak et al. investigated the effect of additives in granulating liquid on sphericity of pellets prepared by extrusion-spheronization.93 Long, dumbbell-shaped pellets were obtained with viscous granulating liquids. However, short, nearly spherical pellets were obtained with watery granulation liquids with calcium chloride that reduced the swelling ability of sodium alginate (Fig. 8). The higher amount of 3% calcium chloride in the formulation showed higher mean dissolution time resulting from the cross-linking properties of calcium ions to the negative charges of alginate molecules. The inclusion of various levels (6% and 8%) of sodium carboxymethylcellulose (SCMC) in the wet cake of MCC prior to drying was assessed in terms of their ability to form pellets by a standardized extrusion-spheronization process, has been assessed. These were then compared with a standard grade of MCC (Avicel PH 101) in terms of the ability to produce pellets containing 80% of the model drugs of low (ibuprofen), intermediate (lactose), and high (ascorbic acid) water solubility. Their ability to retain water with applied pressure using a pressure membrane technique and their ability to restrict water migration during extrusion with a ram extruder were also assessed. The two new types of MCC (B 6 and B 8) were able to form goodquality pellets with all three model drugs, whereas Avicel PH 101
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could not form pellets with this high level of ibuprofen. This improved performance was related to the ability of the new types of MCC to hold higher levels of water within their structure and to restrict the migration of water in the wet mass when subjected to pressure applied during the process of preparing the pellets. There is evidence to show that the two new types of MCC can function over a wider range of water contents than Avicel PH 101.94 Thus, the amount and type of wetting agent employed as the granulating liquid are highly dependent upon the composition of the powder blend. The presence of a binder also affects the amount and type of granulating fluid required.
VI. FORMULATION VARIABLES

Formulation aids or excipients are added to pharmaceutical dosage forms mainly to produce satisfactory delivery of the drug to the intended site, to impart favorable characteristics to the dosage forms, and to facilitate the manufacture of the product. Thus, the selection of a proper excipient deserves consideration because it is usually the excipients that bring about the formation of pellets of suitable strength and integrity. The excipients not only affect the interplay between physical and mechanical forces during pellet formation, but also influence the growth mechanisms of the pellets manufactured by the various processes. Consequently, pellet hardness, friability, size, shape, and dissolution characteristics depend largely on the properties of the excipients used.95 Examples of excipients that are commonly used during the manufacture of pellets are given in Table 2.
VI.A. Microcrystalline Cellulose

Microcrystalline cellulose has been studied extensively as an extrusion-spheronization aid.4,37,95 Avicel PH 101 has come to be regarded as an essential formulation component for successful extrusionspheronization.96 It has been proposed that MCC adds to the tensile strength of the wet mass through autoadhesion (the interdiffusion of free cellulose polymer chains). It is autoadhesion that makes pellets composed of neat MCC hard, noncompressible, and nondisintegrating upon extrusion-spheronization.96 To explain the process of the production of pellets by extrusionspheronization, Kleinebudde has proposed a crystallite-gel model.97
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TABLE 2.
Fillers
Examples of Commonly Used Excipients

Calcium sulfate Dibasic calcium phosphate Lactose Mannitol Microcrystalline cellulose Starch Sucrose Gelatin Hydroxy propyl cellulose Hydroxy propyl methylcellulose Methylcellulose Polyvinyl pyrrolidone Sucrose Starch Calcium stearate Glycerine Hydrogenated vegetable oil Magnesium stearate Mineral oil Polyethylene glycol Propylene glycol Alginates Croscarmellose sodium Crospovidone Sodium starch glycolate Pregelatinized starch Polysorbates Sodium lauryl sulfate Microcrystalline cellulose Microcrystalline cellulose/sodium-carboxymethyl cellulose Colloidal silicon dioxide Magnesium stearate Starch Talc Ethyl cellulose Shellac Carnauba wax
Binders
Lubricants
Disintegrants
Surfactants Spheronization enhancers Glidants
Release modifier
Adapted from Harris and Ghebre-Sellassie.95
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In this model, it is proposed that during granulation and extrusion, MCC particles are broken down into smaller particles and possibly ultimately single crystallites in the presence of water. Colloidal sizes form a gel, and it is the gel network that aids both extrusion and spheronization. According to the sponge model, each particle of MCC would behave as a porous sponge and each particle would be able to absorb a large quantity of water.98 Under pressure, the water would be partly squeezed out but could be taken up again after releasing the pressure while the volume increases. MCC particles remain intact during the processes of wet-granulation and extrusionspheronization, and should be of the same size, shape, and volume in the finished product compared with the original MCC powder. While it is well established that MCC has unique properties as an extrusion aid, there is no model that would sufficiently explain its specific role. The above-mentioned models may hold true in some cases but not in others. When mixtures of drug and MCC are extruded and spheronized, the MCC acts as a matrix from which the drug can slowly dissolve.99 Coating the pellets, using other ingredients in the pellet formulation, or both can further control drug release.9,100 MCC void volume and packing properties play an important role in determining water retention and release during extrusion-spheronization.70 This property dictates to a large extent the water requirement of the MCC grade and, subsequently, the pellet qualities. The degree of polymerization (DP) of MCC and other cellulose materials also influence the extrusion-spheronization process.33 Cellulose types with a high degree of polymerization value showed greater pellet size after homogenization than the types with a low DP value. During the extrusion process, water content in the extrudate and the pellet porosity were increased as the DP was increased for extrudates at the same level of power consumption. Based on these results, it was postulated that the sponge model is more appropriate for the cellulose type with high DP (powdered cellulose), whereas the gel model is more applicable to cellulose types with lower DP (MCC). Lindner and Kleinebudde found a similar result: pellets obtained with powdered cellulose (high DP) showed higher porosities and faster dissolution rates compared with those made with MCC.44 Law et al. compared Avicel PH 101 and Pharmacel 101, and found that Avicel PH 101 was superior, which may be related to its smaller particle size with fewer aggregates, improved flow, lower
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depolymerization temperature range, and absence of traces of cellulose II in its cellulose I content.101 Avicel also appeared to be less sensitive to minor variations in moisture content likely to be encountered in use, and therefore produced pellets that more readily retained their desired size range. A higher yield of undesired large pellets and a wider range of sizes were obtained with Pharmacel compared with Avicel over similar experimental conditions. MCC is also less adversely affected by variations in added water; the spheroid qualities are less sensitive to water content as the proportion of Avicel PH 101 is increased in the mixture.21,102 Different grades of MCC show different extrusion-spheronization behaviors.21,22,70,101,103 Some control over pellet porosity can be exerted by the selection of the cellulose grade used.22 Pellets prepared with Avicel of larger particle size had higher porosities than those prepared with Avicel of smaller particle sizes. Koo and Heng reported that with an increase in the density of MCC grade used, the sphericity of the pellets decreased owing to more resistance of the MCC toward the forming and shaping forces involved during the spheronization process.103 MCC grades with higher tapped densities produced pellets showing poorer flow properties. MCC grades with high packing densities produced pellets of higher bulk and tapped densities at lower water contents. Thus, at lower water contents, MCC packing and void volumes play a role in determining pellet-packing densities. However, as pellet size increases with higher water content, the influence of MCC-tapped densities on packing properties of the pellets diminishes as pellets become larger. Sinha et al. studied a range of MCC grades, and showed that higher grades of MCC used, such as Avicel PH 101, produced the best pellets.103 Variables that may influence the quality of the final pellets including the type and concentration of binder, the type of extruder, extrusion speed and temperature, spheronization speed, and drying time and method were kept constant. It has been shown that MCC can be formed into spheroids over a wide range of drug:MCC ratios, largely due to the favorable plastic rheological characteristics of the MCC/drug/water pastes that are formed. Pellets formed with MCC have been proven many times37,104 (since those early studies) to be dense and spherical, to possess a narrow size distribution, and to display good release characteristics for active drugs. Although MCC is the most widely used excipient in extrusionspheronization, it does have some limitations. The pellets prepared from MCC usually do not disintegrate, leading to diminished drug
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release, especially for poorly soluble drugs.105 Slow dissolution of the pellets formulated with MCC has also been attributed to the pronounced contraction of the pellets during the drying phase, which leads to reduced porosity and thereby hinders entry of the dissolution medium into the pellets.106 Basit et al. reported stability issues of ranitidine with MCC when used in excess of 60%.107 The presence of water is essential for formulating spheroids using MCC, which poses a limitation for moisture-sensitive drugs.108 Water content needs to be optimized with different grades of MCC, as they cannot be interchanged.109 Owing to these drawbacks, various other excipients have been used in the process of extrusion-spheronization. Pellet properties vary by using different grades of MCC, and any one of these can be used depending upon the requirements in regard to such factors as size, shape, and drug release. Avicel PH 101 is the most commonly preferred among the various grades of MCC used in extrusion-spheronization.
VI.B. Other Types of Excipients

In addition to MCC, various other polymers have also been used to facilitate pellet formation by extrusion-spheronization, although with different types of formulation parameters.100,110112 Montousse et al. prepared pellets of gelucires by extrusion-spheronization.113 A hydrophobic gelucire type (50/02) and a hydrophilic type (55/18) were used to sustain the release of theophylline, a water-soluble drug. Castor oil and ethanol were used as the wetting fluids. The hydrophilic gelucire produced good-quality spheroids, whereas Avicel had to be added to the granulation matrix to produce the hydrophobic type of pellets. MCC, along with theophylline, Eudragit 4135F, and PEG 8000 were used for the preparation of pellets by extrusion-spheronization.114 Extrusion was carried out by a hot melt extrusion technique and the extrudates were spheronized at an elevated temperature to achieve pellets of the desired quality. Kojima and Nakagami did not use MCC for the preparation of pellets and carried out extrusion-spheronization by subsequent annealing with water-insoluble polymers, ethylcellulose, and hydroxypropylmethylcellulose (HPMC) acetate.110 Triethyl citrate was used as the plasticizer. Both of the pellets were suitable enough to be used as controlled-release carriers. In pellets containing Carbopol and MCC, the mean pellet diameter was influenced by the ratio of the two ingredients in the blend.39 Neau et al. used Carbopol as a release-modifying agent in pellets containing MCC.100
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Increasing the content of Carbopol in the formulation resulted in a significant reduction of the percentage of drug released. It was also found that a high amount of Carbopol in the blend resulted in the highest-quality pellets. Likewise, HPMC, SCMC, HPC, or PVP aided the process of extrusion-spheronization of MCC.115 However, among these, HPC and PVP were the most satisfactory because they had the least adhesive strength, favoring maximum yield of highest-quality pellets. The use of -cyclodextrin, even at a content of 90% w/w, also produced satisfactory pellets.116 Villar-Lopez et al. prepared the complex of triamcinolone with -cyclodextrin to incorporate more than 90% of the drug in the pellets.117 Otherwise, more than 80% -cyclodextrin in the formulation resulted in unextrudable pastes even at lower water contents. The complex formation procedure increased the proportion of triamcinolone released by the 15:80 (MCC:-cyclodextrin) formulation from 49% to 53% in spite of a parallel increase in granule diameter from 638 to 1042 m. An increase of plain -cyclodextrin content in granules reduced granule size. Law and Deasy examined the different classes of excipients for extrusion-spheronization.102 Among the various silicates examined, a model mixture of MCC and lactose wetted with water, Kaolin, talcum, and Veegum F provided improved plasticity for the formation of spherical pellets. Weak bases such as sodium bicarbonate and weak acids such as fumaric acid also aided spheronization. Waxy materials such as hydrogenated caster oil and Precirol ATO 5, and wetting agents such as sodium lauryl sulfate improved sphericity but reduced yield due to agglomeration. Bentonite, citric acid, and tartaric acid also promoted the production of oversized pellets. Tho and coworkers produced pellets from pectin by extrusionspheronization and identified factors influencing the process and the characteristics of the resulting product.118 They found that spherical pellets could be obtained by using ethanol as the granulating liquid. Steckel and Mindermann-Nogly demonstrated that the chitosan pellets using MCC (070% w/w) as an additive could be prepared by extrusion-spheronization using diluted acetic acid solution as the granulating liquid, wherein chitosan was expected to be dissolved, resulting in a gel-like wet mass.119 The authors concluded that by using demineralized water as the granulation fluid, pellets with a maximum of 50% w/w chitosan could be produced. The mass fraction of chitosan within the pellets could be increased to 100% by using diluted acetic acid for the granulation step. Charoenthai et
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al. reported that the spherical pellets with a maximum fraction of 60% w/w chitosan could be produced when 1.252.5% w/w sodium alginate was included in the formulations with no MCC.120 Thommes and Kleinebudde proposed the use of k-carrageenan as an alternative pelletization aid to MCC in the extrusion-spheronization process.121 Chatchawalsaisin et al. have shown that it is possible to incorporate the glyceride, glyceryl monostearate (GMS), into pellet formulations at a level of at least 30% and still produce round pellets without reducing the in vitro drug release.122 The formulations required less water than those containing MCC alone as the spheronization aid. The inclusion of GMS also offers the opportunity to incorporate drugs that are water insoluble or are poorly permeable through the gastrointestinal membrane into the nonaqueous phase of the formulation. The presence of GMS did not influence this effect. GMS is not a pure material; even the Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and the United States PharmacopeiaNational Formulary (USPNF) differ in their standards. The question arises, therefore, do these allowable differences change the performance of the products, and would other types of glycerides used in pharmaceutical formulations (e.g., as absorption enhancers) perform in the same way? To investigate these issues, Newton et al. used a previously reported successful formulation that contained a model drug (10% diclofenac sodium) with a range of glycerides as an additive (30%), MCC (60%), and water.123 As a comparison, a formulation containing 10% drug with 90% MCC was reported as a standard. The results showed that variability in the type of GMS does not alter its ability to function as an enhancer of pellet formation by extrusion-spheronization. For three different types of glycerides, the water level required to provide smooth regular extrudate at equivalent extrusion forces, which readily form spherical pellets, was the same and is considerably less than that required with MCC alone, which may have implications for the stability of some drugs. The replacement of the GMS with Imwitor 742 allowed an even further reduction in the quantity of water required for pellet formation. Thus, pharmaceutically acceptable glycerides provide an additional option when it comes to the formulation of pellets by extrusion-spheronization. It was also possible to prepare the pellet formulations by dispersing the drugs in molten GMS, grinding, and processing this with MCC and water. Such systems retained the processing characteristics of
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the composition made by the blending of the powder. The presence of GMS reduced the quantity of water required for the process to function. The steady state, or the mean of the range of the forces observed during forced flow, was dependent on the composition and the quantity of water added. The surface of the extrudate appeared smooth and of narrow size range. The extrudate diameter was found to increase with the quantity of GMS in the formulation.122 Prieto et al. evaluated the possible use of starch and agglutinant mixtures as principal excipients for extrusion-spheronization pellets.92 Their results showed that starch (corn or wheat) plus 20% white dextrin yielded high-quality pellets with good size and shape distributions. Bommareddy et al. explored the use of calcium chloride to overcome the tack problem associated with wetted Carbopol 974P resin in a bead dosage form manufactured by extrusion-spheronization.124 They confirmed that this ionic interaction with the drug affects the behavior of the wetted Carbopol. In addition to the drug release profiles, bead average diameter, roundness, friability, and density were also determined. Howard et al. presented a means to produce extruded-spheronized beads devoid of MCC and with a high drug load (greater than 80% w/w). Immediate-release bead product with a high yield (greater than 60% of 1-mm diameter beads) and low friability (mass loss less than 4.0%) that were spherical to the naked eye (roundness score less than 1.20) were obtained.125 The formulation consists only of water-soluble components, taking advantage of the properties of soluble polyethylene oxide (PEO) and methoxypolyethylene glycol (MPEG). This approach incorporates minimal processing aids, with wetted PEO providing the apparent plasticity and cohesiveness and MPEG550 providing the apparent self-lubricating characteristics necessary for successful extrusion and subsequent spheronization into beads. The success of this approach has important implications in cases in which high-drug-load beads are desired, but MCC cannot be used due to chemical incompatibility or complete release cannot be achieved with MCC-containing beads. Chatchawalsaisin et al. reported the use of sodium alginate alone (up to 16%) or in combination (4%) with chitosan to produce pellets by a ram extruder.126 Sriamornsak et al. investigated the possibility of producing two types of sodium alginate-based pellets by a basket extruder, and also of improving the formation of spherical alginatebased pellets by investigating the effect of additive in granulating liquid on characteristics and drug release from resulting pellets.127
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Different sodium alginate types responded to shape modifications to a different extent. Sriamornsak et al. evaluated the effects of amount (i.e., 1050% w/w) and type of sodium alginate and the addition of either calcium acetate or calcium carbonate (0%, 0.3%, 3%, and 10% w/w) on pellet properties such as size, shape, morphology, and drug release behavior.128 The results showed that the amounts of sodium alginate and calcium salts influenced the size and shape of the obtained pellets. However, different types of sodium alginate and calcium salt responded to modifications to a different extent.
VI.C. Binders
The selection of a suitable binder and its concentration is a critical formulation variable during pelletization. During wet massing for extrusion or granulating, the binder is usually added as a liquid. Initially, it is the liquid bridges that hold the particles together; however, as the liquid evaporates, the precipitation and hardening of the binder takes over as the main bonding force. Soluble constituents may also crystallize and contribute to the bonding mechanisms.95 The replacement of MCC in a formulation containing 30% paracetamol with two grades of powder cellulose (a fine powder Elcema P 100 and a granulated powder Elcema G 250) required the addition of a binder for processing.44 The formulations appeared to be equivalent in terms of extrusion performance but differed in spheronization. The best formulation contained Elcema P 100 with 1% binder. Rodriguez et al. found that porosity deviation of pellets prepared with two diluents, MCC and dicalcium phosphate dihydrate, increased with the addition of binders (gelatin and methacrylic polymer).129 Likewise, an increase in binder concentration increased the particle size.56 Pellets using HPC-M as a binder at high spheronizer speeds showed spherical shape, narrow size distribution, and good flow properties compared with Methocel E15LV, HPC-L, and Methocel A4M. The structure of pellets can be markedly influenced by the composition of the granulation liquid.31 Shah and colleagues found that pellets prepared with 40% 2-propanol in the propanol/water mixture (used as the granulating liquid) resulted in a rapid dissolution rate of the pellets, which was caused by the rapid and complete disintegration of the pellets compared with those obtained with a lower amount of 2-propanol in the mixture. This phenomenon was due to a change in the particle bonding of the pellets at concentrations of 40% 2-propanol. The analysis of the pore system in terms of fractal
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dimensions implied a dependency of the fraction of 2-propanol in the granulation liquid on the pore structure. Likewise, water-granulated MCC containing formulae resulted in strongly bonded, hard pellets with good shape; however, pellets with lower strength and less uniform shape did result as the level of ethanol in an ethanol/water granulating fluid increased.68 MCC could not be processed into pellets using absolute alcohol. The difference in bonding strength due to water or ethanol was also shown by the fact that pellets with pure water exhibited less compressibility, whereas the 95% ethanol granulated pellet formulations were reasonably compressible. Sriamornsak et al. showed that the type and concentration of binder affected the appearance of the resulting pellets.130 Increasing the volume of binder solution increased the mean size of the pellets but decreased the yield in the desirable pellet size range. When lower amounts of binder solution were used, spherical pellets were not obtained. The use of an excess amount of binder gave rod-shaped pellets. The addition of 50 g of 1% PVP to 100 g of powder blend gave an optimum yield of spherical pellets in the required size ranges. The type and concentration of binder plays an important role in pellet properties alone and/or in combination with the granulating liquid; therefore, the selection of a suitable binder and granulating liquid and their concentration is required for consideration in pilot scale-up studies.
VI.D. Influence of Drug

Apart from the properties of the excipients, the properties of the drug used also play a very important role in the quantity of water required to form satisfactory pellets and on the physical characteristics of the pellets.28,131,132 The presence or absence of drug was important in influencing the mean diameter of the pellets.39 Generally, formulations that contain a low proportion of drug are easy to spheronize, and water-insoluble drugs are easier to spheronize than water-soluble drugs.4 A quantitative relationship was identified between the quantity of pellets in the 11.4 mm size range and the solubility of the drug.28 Hileman et al. predicted the drug solubility effects on the quality of pellets.131 A strong linear relationship was observed between the aqueous solubility of the drug and the water content required for optimum pellet formation. For poorly soluble drugs, the water content range over which quality pellets could be produced was much
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broader. Lustig et al. demonstrated that, for a series of model drugs mixed with equal parts of MCC, the quantity of water required to form the best-quality spheres decreased in a linear manner with an increase in the log of the drug solubility.133 Using cluster analysis, Tomer et al. indicated that the level of water and type of model drug were the most significant factors in determining the particle size.27 The processability and properties of pellets containing five different drugs of similar chemical structures also showed significant variance. From this observation, the authors concluded that the prediction of satisfactory pellet formation from drugs with similar chemical structures was not possible; it appears that numerous unidentified factors are also involved in the production of satisfactory pellets.27,134 Jover et al. studied 20 model drugs at a level of 80%; in all cases pellets could be produced, and a best level of water was identified for each drug.134 Like Tomer et al., Jover and colleagues also could not find any satisfactory relationship between the drug properties such as pKa and freezing point depression and pellet properties. They also could not find any relationship between solubility of the drug and pellet qualities, which may have been due to the high percentage of drug used. The particle size of the drug also influences the pellet properties. Fielden et al. showed that as the particle size of the model drug increased, water movement within the formulation increased, resulting in a tendency of the pellets to agglomerate on the plate.85 This hypothesis was supported in a separate study in which reducing the water content or using a gravity-fed extruder allowed successful pellet production.43 Pellets have been prepared by extrusion-spheronization containing MCC and four model drugs with decreasing order of solubility paracetamol (P), diclofenac sodium (D), ibuprofen (IB), and indomethacin (IN) at a 10% level with and without the addition of a range of levels of glyceryl monostearate (GMS). The drugs differed in their response to extrusion in that all formulations containing the drug D had a steady-state extrusion profile, whereas the other three drugs exhibited forced flow, indicating the possibility of water migration during the process of ram extrusion. The presence of GMS did not influence this effect. The drug D also required consistently less water to function than the other three drugs.122 In another study, the release of different actives from Carbopolcontaining beads was compared.124 Caffeine was released faster than chlorpheniramine maleate from these beads, although chlorphe-
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niramine maleate is more soluble (160 mg/mL) than caffeine (20 mg/ mL). This result was initially surprising because faster release from a matrix system is expected with a drug possessing a higher solubility when all other characteristics are comparable. The nonelectrolytes in the study, caffeine and dyphylline, were released at approximately the same rate, even before the swelling and gelling of Carbopol was visually observed, although the solubility of dyphylline (333 mg/ mL) is substantially higher than that of caffeine. The slower release seen with chlorpheniramine maleate was presumed to be due to the interaction of its protonated amine with the carboxylate groups of Carbopol after the polymer had hydrated and gelled. Paker-Leggs and Neau examined the drug release rates from extruded-spheronized beads containing Carbopol, which have been shown to be dependent on the chemical nature of different types (free-base, hydrochloride, and maleate forms) of drugs.135 Different forms of model drug resulted in different bead average diameter, roundness, and smoothness, but the ruggedness was not affected. Release profiles for the two salt forms were nearly superimposable, but the free-base form was released more slowly. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation were contributing factors to the release mechanism in each case, although polymer relaxation was more influential with the free-base form. In light of these results, Paker-Leggs and Neau concluded that the choice of the form of a drug should be considered carefully when preparing Carbopol-containing beads produced by extrusion-spheronization. It has been found that there is a great correlation between the properties of the drug used such as solubility in water and particle size and the amount and type of the granulating liquid required, size, shape release, and yield of the pellets. Pellet quality is also affected by the type and amount of excipients used with regard to the drug used for pellitization.
VII. EVALUATION OF FINAL PELLET QUALITY

The pellets formed by extrusion-spheronization are evaluated by various parameters such as size distribution, shape, friability, density, porosity, and flow properties, which are discussed below.
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VII.A. Size Analysis

Mean particle size of the pellets is a very important parameter and is often used as a response variable in optimization studies of pellets involving extrusion-spheronization.11,21,22 It is generally performed by using sieve shaker with a series of standard sieves. The process variables that affect the particle size are the extrusion screen, spheronization time and speed, drying technique, and temperature. The various formulation variables reported to influence the pellet properties are moisture content, binder type and its concentration, and excipients. When the extrusion screen of a small mean hole diameter was used, small pellets were obtained.14 Mean particle size also varied according to the type of extruder used.43 To produce pellets of equivalent size, a ram extruder required different water content than a gravity-fed extruder. Various studies have investigated the effect of spheronization load, speed, and time on mean pellet size.21,22,29,55 The effect on the mean pellet size due to plate geometry has also been studied.47 Mean size of the pellets is also influenced significantly at the last stage of spheronization: drying. The higher the temperature employed for drying, the smaller the diameter.58 In addition, the pellets were larger when they were freeze-dried57 or dried in a microwave oven.58 The size of the pellets is also dependent on the formulation parameters, especially on moisture content and the type and amount of binder employed during granulation, which was discussed in Section VI.C. Podczeck et al. determined the Feret diameter, the longest diameter and projected area (A) from the pellet images.135 The Feret diameter of a pellet is defined as the average of 36 caliper measurements around the particle employing a 5 angle of rotation. The projection sphericity (PS) of a pellet was calculated according to the following formula:
where dL is the longest caliper distance observed when tracing around the particle. A perfect sphere will have PS = 1.
VII.B. Sphericity
One of the most important characteristics of pellets is their sphericity, which raises an important issue of how to assess this important
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parameter.4 The shape, area, aspect ratio, and perimeter of core pellets are usually investigated by optical microscopy image analysis. This is a complex issue, and many publications that claim to deal with a spheronizing process fail to provide a quantitative answer to validate their claims. A visual record of the change in granule shape was obtained by taking high-speed photographs of the spheronization.82 However, this method did not provide any quantitative estimation of the spheroid sphericity. Lovgren and Lundberg proposed the concept of aspect ratio, which is the ratio of the longest to the shortest dimension of the particles,48 which they related to an overall proportion to represent the sphericity of the pellets. However, a circle, square, or other polygonally symmetric shape will have an aspect ratio of 1.0, because in these examples, the length and breadth are equal. The two parameters, the aspect ratio and the pellet circularity, were computed using the formulae given below, where A and P stand for the projected area and the perimeter of the pellet, respectively, as recorded using the software from the digitalized image.
Chapman et al. characterized the sphericity of the pellets in terms of the angle necessary to tilt a plane such that the particles would roll, the One Plane Critical Stability (OPCS).137 The method is based on determining the center of gravity of the particle from a digitized image of the coordinates of its outline, and computing the angle necessary to incline a plane such that the center of gravity moves outside the boundary of the particle. This method is superior to the aspect ratio and provides clear evidence that it is sensitive enough to detect large deviations from circularity but is less able to differentiate between slight changes in circularity.4 This method does not consider the aspects of surface texture of the objects. Surface texture distribution and shape, however, can be characterized using fractal geometry.138 The distribution of the geometric shapes and surface irregularities of particles139 and soil granules can be related to their application properties.140 However, for fractals, there is no exact number applicable to distinguish between spherical, polygonal, or unorganized particles.
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Podczeck and Newton developed a shape factor, eR, based on the deviation of shape from a circle toward an ellipse and surface irregularities141:
where re is the average radius of the particle, Pm is the measured perimeter of the particle, l is the length of the particle, and b is the breadth of the particle. eR is able to detect small deviations from circularity and differentiates between more or less elliptical figures. This value also differentiates between different polygonally symmetric figures, even when the aspect ratio provides equal values. Koo and Heng used a simple technique to describe the shape of pellets using the following formulae103:
Using the above formulae, the overall shape of any particle can be characterized and quantitated. Neau et al. calculated the roundness of pellets by using the following formula100:
where P is the perimeter of the bead image and A is the area determined by the total number of pixels within the feature. The factor 0.9399 corrects the perimeter for the effect of the corners produced by digitization of the image. A roundness value of 1.0 corresponds to the image of a perfect sphere, and higher values correspond to less spherical images.
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In the truest sense, all of the methods described above give only an estimation of the roundness or circularity of the pellets and not their sphericity. Image analyzers and specially designed computer programs are needed to calculate the data to arrive at a statistically significant conclusion. However, unfortunately, all of the image analyzers take only two-dimensional images of the objects, from which only the circularity can be estimated. Therefore, there is a need to develop three-dimensional imaging systems and tailor the existing formulae appropriately to arrive at a concrete conclusion of the pellet shape.
VII.C. Friability and Granule Strength

There are various factors that may affect granule strength. Larger granules may possess greater strength than the smaller ones142; it would appear that smaller granules are more poorly formed and less robust than their larger counterparts. The amount and type of binder used in the granulation also affect the granule strength. Other factors include the moisture content,70 the excipient used, the drying temperature of the prepared pellets,58 the drying method of the prepared pellets,58 and the type of base plate in a rotary spheronization process. The basic principle of measuring the granule strength is more or less similar to the measurement of the compression strength.142 In this test, a granule is placed between anvils and the force required to break the granule is measured. If pellets are to be compacted, it is important to know something about the mechanical properties of the pellets with respect to how they respond to the application of the forces during compaction. Friability determination typically involves taking granules that are known to be greater than a particular mesh size. The granules are then placed in a container that is tumbled or shaken for a predetermined time with or without additional attrition. The material is again shaken on a screen of that particular mesh size. The percentage of material passed is taken as a measure of granule friability as determined by the following equation143:
where %F is the percentage friability; wi is the initial weight of granules before friability testing; and wr is the weight of granules retained above the sieve after friability testing.
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Various researchers have used different types of equipment (friabilators or tumblers) for different times and with different speeds. Both glass balls22,45 and steel balls have been used along with the pellets as the attrition agents and the friability of the granules was tested on a shaker at maximum amplitudes.49,56 The dimension of the balls, their weight, and rotation speed of the equipment also varies between researchers, which does not facilitate the comparison of all the results. Lindner and Kleinebudde found that for the same batch of pellets, different friability values were obtained by using different methods.44 When they used the method reported by Zhang et al.,13 the friability values were less than 0.01% with an unacceptable reproducibility. For the same batch of granules, when Lindner and Kleinebudde used the method reported by Korber and Moest,144 the friability values were below 0.1%. The large variation in the data did not allow a model to be fitted. Lindner and Kleinebudde did not find any correlation between porosity and friability44 but Perez and Rabiskova did.58 Similarly, even as the former found a significant decrease in percentage friability by increase in binder concentration, Umprayn et al. did not.56 For the determination of granule strength, Kojima and Nakagami used a particle hardness tester and calculated the granule strength by the equation that was first given by Hiramatsu110,145: St = 0.7 P / (d2/4) where St is the granule strength, P is the strength when the granule broke, and d is the diameter of the granule. Using the process of extrusion-spheronization, Bashaiwoldu et al. designed MCC pellets to vary their mechanical properties by the incorporation of lactose, GMS, ethanol, or glycerol.28 The tensile strength, deformability, linear strain, elastic modulus, and shear strength of the coated (aqueous dispersion of ethyl cellulose) and uncoated pellets were determined by conventional techniques, including a diametral compression test of individual pellets and compaction of a bed of pellets. The authors demonstrated that the coating film affected the mechanical properties of the pellets differently depending on the properties of the core pellets. Analysis of variance established a significant increase in the strength of the soft GMS- or glycerol-containing pellets with coating, whereas the effect of the coating material was not significant with respect to the elastic modulus, storage modulus, and phase angle of such pellets. During spheronization, as water evaporates, dissolved substances in the pellets may migrate to the surface and form a crust that
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provides a barrier to further moisture transfer, thereby trapping some water in the pellets. The low level of trapped water makes a significant contribution to the strength of the pellet by forming liquid bridges.3 On drying, however, a porous pellet with reduced mechanical strength may be produced. Dyer et al. suggested that the resistance of individual pellets to crushing is related to the cohesive and adhesive properties of the excipients, their size and shape, as well as other properties that are specific to the manufacturing process.146 The crushing strength of the pellets can be determined by using a universal compression tester. The maximum crushing strength (m) is calculated from the maximum applied load and the cross-sectional area of a pellet as described in the following equation: m = 0.4Pm / r2 where Pm is the maximum load at failure (N) and r is the radius of the spherical pellet (m).146 Abbaspour et al.91 evaluated MDT, crushing strength, elastic modulus, surface characteristics, sphericity, and aspect ratio of pellets composed of Eudragit RS and Eudragit RL (1:0, 1:1, 0:1) and % PVP (1, 3, 5). Increasing the percentage of PVP slightly decreased MDT and elastic modulus but had negligible effect on crushing strength. Increasing the percentage of drug up to 60% decreased MDT but beyond that increased MDT.91 Increasing the percentage of drug also decreased the elastic modulus of the pellets. Eudragit RL PO compared with Eudragit RS PO resulted in pellets with high crushing strength; however, the Eudragit type did not have a significant effect on elastic modulus. Cespi et al. evaluated crushing strength and stress relaxation tests as mechanical properties of different ratios of microcrystalline cellulose and lactose monohydrate pellets to verify if these parameters could be used to predict the pellets aptitude to be compressed or used differently.147 The viscoelastic properties of a solid material can be determined by a uniaxial compression device using two kinds of transient tests: creep and stress relaxation. In the first test, one step of stress is applied and the change in strain is measured for a certain period of time; in the second test, a constant strain is applied and the stress is measured for a certain period of time. The reason that the stress relaxation test was chosen in this study was because the contact surface between the pellet and the probe remains constant for the entire test (i.e., the imposed strain is constant), so the stress is always proportional to the measured force. This statement is valid only when all of the pellets are very similar in shape and size.
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Crushing strength tests provided information of both the mechanical strength and the fragmentation aptitude, whereas the stress relaxation tests provided information about their deformation ability (viscous flow) and residual elasticity (stress relaxation modulus). Cespi et al.147 concluded that the granule crushing strength was extremely useful in predicting the fragmentation aptitude of the pellets. It was pointed out that the presence of a higher amount of lactose induced fragmentation in the pellets and at the same time decreased the pellet crushing strength. The stress relaxation test performed on the different batches of pellets allowed a direct comparison of their deforming behavior. The relaxation time and the relaxation modulus were not proportional to the pellets composition but they were minimal at a particular lactose-cellulose ratio. Single pellet mechanical properties such as tensile strength (or crushing strength) and elastic modulus28,53,62,148154 and their influence on compression behavior and tablet properties60,155157 are important transient rheological parameters as factors for the prediction of the pellets ability to be compressed into tablets. In addition, among these parameters, those concerning the deformation ability could be used to distinguish among different formulations of pellets in order to choose those more suited to sustain the stress that a coating undergoes when coated pellets are compressed. In fact, as previously stated, pellet characteristics are fundamental. Deforming pellets are more suited than fragmenting pellets.
VII.D. Density
Bulk density is indicative of the packing properties of particles and is greatly influenced by the diameter of the spherical granules. The tapped density of pellets, the quotient of the weight of the pellets and its final volume after tapping until the time when the volume does not decrease anymore, can be measured using an automated tapper. Bulk density is dependent on particle packing. Loosely packed pellets have greater arch strength due to the formation of bridges and therefore may be considered more resistant to flow. The interlocking of nonisometric or less spherical, highly textured pellets will more readily form arches or bridges within the bed. This tendency for irregular pellets to produce open structures causes them to have a larger difference in density between tight packing (tapped) and loose packing (poured) geometries than more regularly shaped spheres, resulting in larger Carrs indices (described below). The above con-
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siderations assume negligible electrostatic interaction between the pellets and handling in a consistent manner. Granule density indicates the extent of densification or compactness of substances. It can be measured by the solvent displacement method at low pressures. The granular volume includes the pore volumes of the particles. The true volume is the difference in the granule volume and the pore volumes. The true volume can be measured by a pycnometer. The quotient of the tapped density to its bulk density is known as the Hausner ratio (HR)158:
where t is the tapped density, and b is the bulk density. A high Hausner ratio indicates increased cohesion between particles and, therefore, poorer flow.24 Carrs index (Ic) can be calculated as given below159,160:
Ic = (t b) / b.
Carrs index indicates the percentage compressibility involved and lower values indicate better flow of the granules. In this case, compressibility is a misnomer as no compression is involved.102 The densities of pellets may affect other pharmaceutical processes or factors as described below143: Most pellets are filled into hard gelatin capsules volumetrically using automated capsule filling machines. If the density of the pellets varies significantly from batch to batch, the potency of the finished capsule will also vary. Any significant variation in the density of pellets will affect the batch size determinations in the coating equipment. During mixing of granules, differences in densities may cause their segregation or inefficient mixing. Many researchers have assessed the influence of density on the gastric transit of pellets.161168 Devereux et al. showed that density can influence gastric emptying and therefore has important implications for the formulation of controlled-release forms.161 They used two types of pellets, one with low density (1.5 gm/cm3) and another with high density (2.8 gm/cm3), as determined by air pycnometry. They studied the mean transit time taken by the pellets to transmit through the small intestine, the time taken for 50% of the pellets to
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empty from the stomach, and the time taken for 50% of the pellets to arrive at the caecum. They found that the heavier pellets were retained in the stomach for a longer time than the lighter pellets. There was, however, no statistical difference in the small intestine transit time and the time for 50% of the pellets to arrive at the caecum. The conclusions drawn by different researchers on the influence of density on GI transit of pellets differ. Bechgaard and Hegermann reported that an increase in density from 1.0 to 1.6 g/cm3 significantly delayed average transit time of pellets in human subjects with ileostomies.1 Bogentoft et al. failed to confirm these differences in normal human subjects with pellets of densities 1.2 and 1.8 g/ cm3.164 Bechgaard et al. found no difference between pellets of densities of 0.94 and 1.96 gm/cm3.163 Kaus et al. administered single units ranging in density from 1.03 to 1.61 gm/cm3 and observed no differences in travel.167 Similarly, Davis et al. found that the mean gastric emptying rates of pellets of densities 0.94 and 1.96 gm/cm3 were not significantly different.165 Kaniwa et al. administered units ranging in density from 1.29 to 1.92 gm/cm3 but did not observe any differences in gastric emptying rate.166 Gruber et al. examined the gastric emptying of units of a much wider density range (0.52.9 gm/cm3) in fasted dogs.162 They concluded that gastric emptying appeared to be independent of density. Sangekar et al. compared the gastric retention of floating (specific gravity 0.96) and nonfloating (specific gravity 1.59) dosage forms.168 They reported that density did not influence gastric retention, whereas the presence of food did in both cases. Granule density and porosity are interrelated and are dependent on the water content and amount of binder.44 Evaporation of water from the pellets leads to the formation of pores. Higher water content during the extrusion process will result in higher porosities and thus lower granule density. With low water content, the effect of the amount of binder was more pronounced. More binder resulted in a product with fewer pores. This effect was minimized at higher water contents.21,44 Pellet densities were calculated for pellets of MCC with different concentrations of moisture.70 A water content of 3540% (w/w) produced pellets with the highest bulk and tapped densities. Beyond this, increasing water content produced bigger pellets that packed less well and showed lower densities. Umprayn et al. also obtained decreased bulk and tapped densities with an increase in the amount of water.56
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Perez and Rabiskova found different granule densities for granules obtained after differing drying temperatures and drying methods.58 At higher drying temperatures the granules shrank, which resulted in higher granule densities. Microwave-drying of the same granules at 130C led to a faster and uniform evaporation of water. Almost all of the water content was evaporated in the first few minutes of the process, and consequently, the matrix structure remained intact in the majority. In this case, the shrinking of the pellets reached the smallest value, which resulted in the lowest granule densities.
VII.E. Porosity
Porosity is a measure of void spaces in a material and can be calculated using a number of techniques, such as density determination, gas adsorption, water displacement, and porosimetry.169 Determination of pore structure can provide important information on disintegration, dissolution, adsorption, and diffusion of drugs.170 Pore diameter and volume, can be measured by gas adsorption and MIP. The gas adsorption method is limited to pore diameters smaller than 2000 , whereas MIP is capable of measuring larger pores and interparticle spaces.171 MIP is based on intrusion of mercury into the pores of a solid sample and is quantified using the Washburn equation172:
Pr = 2 cos
where P is pressure (Psia), r is the radius of the pore (m), is the surface tension of mercury (dynes cm-1), and is the contact angle of mercury. This equation holds true only if the surface tension and contact angle of mercury are kept constant and the shape of pores is assumed circular. MIP has been extensively used in porosity determinations of granules.111,173177 Mehta et al. found a significant effect of various factors such as drug loading, water required for granulation, and spheronization time on the porosity of granules.111 Pellets with low drug loading showed increased pore surface area with small mean pore diameters and an increased number of total pores. Total porosity of the pellets increased with the addition of water for granulation values from 6070% w/w, corroborating reports by other researchers.44,155,178,179 Porosity parameters were also found to change with duration of spheronization. A processing period of 210 min increased the pores and the total pore surface area and decreased the pore diam-
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eter; beyond this time, up to 20 min, none of the porosity parameters was affected. As expected, the dissolution rate of the pellets is also a function of spheronization time. Both the drying temperature and drying method influenced the porosity of granules.5759 Increasing the drying temperature increased shrinkage of the granules, thereby reducing the porosity. When the pellets were dried by different methods, different results were obtained. Microwave-drying excluded shrinking due to immediate water evaporation, as did freeze-drying, which provided pellets of nearly the same dimensions as wet pellets, resulting in an increased porosity.57,180,181 Boutell et al. studied the effect of additives on pellet porosities. Pluronic solutions yielded pellets that were less porous than those produced using water.15 Pellets prepared with glycerol also showed the same effect. Pellets containing barium sulfate were more porous, whereas the use of sodium lauryl sulfate did not influence the porosity parameters. The type of Avicels used in spheronization affected the pellet porosities.22 Avicels of larger particle size produced pellets with larger intraparticular porosities. Increasing the fraction of 2-propanol resulted in higher values for the porosity of the granules.181 A remarkable effect occurred when the granulation liquid contained more than 40% 2-propanol, when the percentage porosity again started to decrease. This was attributed to a transition in the structure and particle bonding of the pellets.
VII.F. Flow Properties

Many methods are available to measure the flow properties of pellets. Some of the common methods are angle of repose, shear strength determinations, and flow-rate measurements. There are many fundamental properties of solid particles that influence their flow properties, such as particle size, particle size distribution, particle shape, surface texture or roughness, residual surface energy, and surface area.141 The angle of repose is commonly used as a parameter for evaluating interparticulate forces of powders or granules.182 Use of high concentrations of polysorbate 80 imparted a degree of tackiness to granules, producing a larger angle of repose and reduced flow velocity.182 With the increase in water content of the granulations, the pellet flow rate decreased.70 With further increases in the water content, the pellets became larger, and subsequently their flow
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through the orifice became poorer. Pellets produced using a very high amount of water (45% w/w) were too large for flow measurements. Mixer torque rheometry (MTR) can be used to characterize the rheological properties or cohesiveness of moistened powder masses during mixing. MTR monitors simultaneously the changes occurring in a powder mass with different binder concentration, mixing time, and speed of the mixer blades. Another torque parameter, cumulative energy of mixing (CEM), can track and reveal changes in the effects of MCC physical properties on the rheological behavior of its moistened masses as water content is increased. Additionally, torque rheological properties of MCC-lactose binary mixtures (3:7) can also be determined and their respective torquemax(blend) and CEM(blend) values derived. Soh et al. demonstrated the feasibility of using torquemax(blend), CEM(MCC), and CEM(blend) values of MCC grades to predict the quality of their resultant pellets, which would, in turn, reflect the performance of different MCC grades in extrusion-spheronization.183 This study explored the feasibility of predicting the quality of MCC pellets prepared by extrusion-spheronization using torque rheological characterization. Soh and colleagues have demonstrated the usefulness of torque rheometry as a simple, reliable, and competent preformulation tool to predict the quality of MCC pellets prepared by extrusion-spheronization.
VII.G. Surface Texture

Morphological examination of the surface and internal structure of the dried pellets can be carried out using a scanning electron microscope (SEM). The surface texture and the inner structure of the pellets strongly depend on drug proportion, composition and volume of the wetting liquid, additives and spheronization, and drying conditions, and critically determine the relevant properties such as friability, flowability, wettability, adhesion to various substrates, and drug delivery behavior.65 Gomez-Carracedo et al.65 concluded that the texture analysis of SEM images and thermodynamic analysis of MIP data provide useful information for a detailed characterization of the surface texture and the inner structure of pellets. The parameters derived from the analysis (Gray-level non-uniformity (GLN) and fractal dimensions of pellet surface and pore surface) enable one to quantify the influence of pellet composition on the roughness of the surface and pores and on the drug release. Image analysis of SEM micrographs is used to extract quantitative information of fractal geometry and surface texture.
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Image texture provides information about the structural order of the surfaces as a function of the intensity, position, and/or orientation of the pixels. To accomplish this, parameters derived from the gray level co-occurrence matrix (GLCM) and from the number of consecutive cluster pixels in a given direction (run-length) (gray-level nonuniformity [GLN]) are used. MIP enables the characterization of pore volume, mean pore size, and pore size distribution. In a pioneering study, the fractal geometry of the pores of pellets was estimated from the pore volume obtained using MIP data and applying the Mengersponge model to the linear section of Richardson plots.181 A precise estimation of volume and surface fractal dimension can be obtained from the analysis of pore surface using the whole cumulative pore volume distribution. This approach has proven to be useful for the evaluation of the roughness of the pore surface of different materials such as coal, silica gel, and alumina particles.13
VIII. CONCLUSION
At present, complete knowledge of all of the operational and formulation variables for the successful design of an optimum multiparticulate delivery system is mandatory. In this review, an attempt has been made to outline the general concepts of pellet preparation by extrusion-spheronization. It is concluded that extrusion operational variables such as screen pressure (extrusion force), screen hole diameter, extruder type, screw speed, and temperature have a high impact on the sphericity and size of the pellets. The relationship between these variables and water content has also been discussed. A decrease in extrusion force was observed with increasing water content. The type of extruder influences the extrude quality and, consequently, the pellet quality. Different types of extruders result in pellets of different properties because of the change in the die length and the force of extrusion. However, screw speed of the extruder seems to have little impact on the final pellet qualities. The type, amount, and quantity of the granulating liquid, excipients, and drug affect both the extrusion and the spheronization processes, thereby influencing the pellet morphology, size, size distribution, plasticity, density, friability, porosity, drug release, surface texture, and flow properties. The solubility of the material used (both drug and fillers) also plays a critical role in determining the quantity required to form the pellets with suitable characteristics. Spheronization load, speed, and time are the major operational variables that affect the quality (pellet diam-
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eter, circularity, etc.) and yield of pellets. The friction plate design, diameter, and speed play a key role in optimizing the final quality of the spheroids. The spheronization process is also temperature and formulation dependent. Finally, the drying temperature and drying technique can have profound effects on the pellet properties (size, circularity, density, friability, flow properties, drug release, etc.). In addition to its use in the manufacture of agrochemicals, detergent additives, and sweeteners in food, the extrusion-spheronization process is gaining popularity in the manufacture of pharmaceuticals, being exploited primarily for the production of oral drug delivery systems with desirable release characteristics.
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coated drug preparations and food on gastric emptying rates in humans. J Pharmacobio Dyn. 1988;11:57175. Kaus LC, Fell JT, Sharma H, Taylor DC. On the intestinal transit of a single non-disintegrating object. Int J Pharm. 1984;20:31523. Sangekar W, Vadino W A, Chaudry I, Parr A, Beihn R, Digenis G. Evaluation of the effect of food and specific gravity on tablets on gastric retention time. Int J Pharm. 1987;35:18791. Rootare HM. A review of mercury porosimetry. In: Advanced Experimental Techniques in Powder Metallurgy. New York: Plenum Press; 1970. p. 22552. Dees PJ, Polderman J. Mercury porosimetry in pharmaceutical technology. Powder Technol. 1981;29:18797. Lowell S, Shields JE. Equivalency of mercury porosimetry and gas adsorption. Powder Technol. 1981;29:22531. Washburn EW. Note on a method of determining the distribution of pore sizes in a porous material. Proc Natl Acad Sci. 1921;7:1156. Juppo AM. Change in porosity parameters of lactose, glucose and mannitol granules caused by low compression force. Int J Pharm. 1996;130:14957. Juppo AM, Yliruusi J. Effect of amount of granulation liquid on total pore volume and pore size distribution of lactose, glucose and mannitol granules. Eur J Pharm Biopharm. 1994;40:299309. Fujiwara H, Toda J, Kato M. Studies on pore structure of granules by mercury porosimetry. Chem Pharm Bull. 1966;14:6017. Nicholson GL, Enever RP. The influence of porosity upon the distribution of reserpine in calcium sulfate granules. J Pharm Pharmacol. 1974;26:4206. Zuurman K, Riepma KA, Bolhuis GK, Vromans H, Lerk CF. The relationship between bulk density and compactibility of lactose granulations. Int J Pharm. 1994;102:19. Jerwanska E, Alderborn G, Newton JM, Nystrom C. The effect of water content on the porosity and liquid saturation of extruded cylinders. Int J Pharm. 1995;121:6571. Sousa JJ. Influence of process conditions on drug release from pellets. Int J Pharm. 1996;144:15969. Habib YS, Augsburger Ll, Shangraw RF. Production of inert cushioning beads: effect of excipients on the physicomechanical properties of freeze-dried beads containing microcrystalline cellulose produced by extrusion-spheronization. Int J Pharm. 2002;233:6783. Schroder M, Kleinebudde P. Structure of disintegrating pellets with regard to fractal geometry. Pharm Res. 1995;12:1694700. Heng PWS, Wan LSC. Physical properties of granulations containing polysorbate 80. Drug Dev Ind Pharm. 1987;13:35567. Soh JLP, Liew CV, Heng PWS. Torque rheological parameters to predict pellet quality in extrusionspheronization. Int J Pharm. 2006;315:99109.
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Extrusion-Spheronization Process Variables and Characterization

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Critical Reviews in Therapeutic Drug Carrier Systems, 26(3), 275331 (2009)

Extrusion-Spheronization: Process Variables and Characterization

0743-4863/09 $35.00 2009 by Begell House, Inc. www.begellhouse.com

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

II.A. Extruder Types

TABLE 1. Types of Extruders and Their Features

Schematic view of an axial type screw extruder.

Schematic view of a radial type screw extruder.

extrusion-spheronization: process Variables

FIGURE 4. Schematic view of a sieve extruder.

Schematic view of a ram extruder.

II.B. Extrusion Operational Variables

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

III.A. Mechanism of Spheronization

III.B. Spheronization Operational Variables

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

V. INFLUENCE OF MOISTURE ON EXTRUSION-SPHERONIZATION

extrusion-spheronization: process Variables

V.A. Evaluation of Rheological Properties of Wet Powder Mass

V.B. Assessment of Water Movement in Extrusion-Spheronization

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

VI. FORMULATION VARIABLES

VI.A. Microcrystalline Cellulose

Examples of Commonly Used Excipients

Surfactants Spheronization enhancers Glidants

Adapted from Harris and Ghebre-Sellassie.95

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

VI.B. Other Types of Excipients

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

VI.D. Influence of Drug

extrusion-spheronization: process Variables

VII. EVALUATION OF FINAL PELLET QUALITY

extrusion-spheronization: process Variables

VII.A. Size Analysis

extrusion-spheronization: process Variables

VII.C. Friability and Granule Strength

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

VII.F. Flow Properties

VII.G. Surface Texture

extrusion-spheronization: process Variables

extrusion-spheronization: process Variables

16. 17. 18. 19. 20. 21.

32. 33. 34.

extrusion-spheronization: process Variables

53. 54. 55.

56. 57. 58. 59.

60. 61. 62. 63. 64.

66. 67. 68. 69. 70.

73. 74. 75. 76. 77. 78. 79.

extrusion-spheronization: process Variables

90. 91. 92. 93.

extrusion-spheronization: process Variables