Critical Reviews™ in Therapeutic Drug Carrier Systems, 26(3), 275–331 (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;
[email protected] 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 0743-4863/09 $35.00 © 2009 by Begell House, Inc. www.begellhouse.com Begell House Digital Library, http://dl.begellhouse.com Downloaded 2010-12-13 from IP 147.8.31.43 by University of Hong Kong Libraries 275 sinha et al. 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 µm 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.5–8 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.13 276 Begell House Digital Library, http://dl.begellhouse.com Downloaded 2010-12-13 from IP 147.8.31.43 by University of Hong Kong Libraries extrusion-spheronization: process Variables and characterization FIGURE 1. Processing flow chart indicating the individual processing variables in the spheronization process using an extruder and a spheronizer. 277 Begell House Digital Library, http://dl.begellhouse.com Downloaded 2010-12-13 from IP 147.8.31.43 by University of Hong Kong Libraries sinha et al. 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,17–19 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 µm is not often encountered.4 Nevertheless, some researchers have used an extruder screen of 400 µm 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. 278 Begell House Digital Library, http://dl.begellhouse.com Downloaded 2010-12-13 from IP 147.8.31.43 by University of Hong Kong Libraries extrusion-spheronization: process Variables and characterization 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 279 Begell House Digital Library, http://dl.begellhouse.com Downloaded 2010-12-13 from IP 147.8.31.43 by University of Hong Kong Libraries The first is an extruder equipped with two contra-rotating wheels. Schematic view of an axial type screw extruder.com Downloaded 2010-12-13 from IP 147. which discharges the extrudate perpendicular to the axis of the screw (Fig. 3). perpendicular with the axis of the screw (Fig.23. one or both of which can be perforated. In the radial type of screw extruder. where an oscillating or rotating device pushes the plastic mass through the screen. 4).43 by University of Hong Kong Libraries . the mass is fed between FIGURE 3.31.23 The screen is positioned at the bottom of the extrusion chamber in the case of a sieve extruder (Fig. In a basket extruder.sinha et al. the granulate is fed by gravity or by a screw into the extrusion chamber. the vertical walls of the extrusion chamber make up the extrusion screen.begellhouse. In the axial type of screw extruder.8. http://dl. the die is placed around the screw.24 In sieve and basket extruders. In the first type of extruder. 280 Begell House Digital Library. Schematic view of a radial type screw extruder. 2). There are two types of roll extruders. the screen is placed at the end of the screw. FIGURE 2. 8. the two wheels and the extrudates are collected inside the extrusion wheels. it is possible to measure the forces during extrusion through the two perforated cylinders.23 With the second type of extruder. These rollers helps to discharge the material outside the cylinder (Fig.25 FIGURE 5.com Downloaded 2010-12-13 from IP 147. 5). Schematic view of a roll extruder with: (A) a single perforated roll.begellhouse. (B) two perforated rolls. 281 Begell House Digital Library.31. http://dl.43 by University of Hong Kong Libraries . which can then be correlated to the final quality of the pellets.extrusion-spheronization: process Variables and characterization FIGURE 4. The second type of roll extruder has a perforated cylinder that rotates around one or more rollers. Schematic view of a sieve extruder. and (C) a set of rollers rotating inside a perforated extrusion screen. B. 2) screen hole diameter. In a 1995 Box-Behnken experimental design study. the maximal yield of 18/25-mesh cut pellets was uniquely related to the screen pressure.15. Shah et al. 282 Begell House Digital Library. 3) extruder type. Finally. 1. 6). have described the instrumentation of a pilotscale gravity-feed extruder.sinha et al. FIGURE 6. are: 1) screen pressure. The force necessary to maintain the set extrusion speed can be measured. stress is necessary to force a wet mass through small orifices.25 A decrease in extrusion force was observed with increasing water content. Extrusion Operational Variables Various variables of extrusion operation that have significant effects on the extrudate. who processed a series of microcrystalline cellulose (MCC)-dicalcium phosphate formulations. measured the screen pressure by tangentially mounting a strain gauge load cell. the addition of lactose or dicalcium phosphate resulted in differing profiles.30 Screen pressure was found to be linearly related to the amount of water used for granulation. Screen Pressure In the process of extrusion. Shah et al. 4) screw speed.com Downloaded 2010-12-13 from IP 147.43 by University of Hong Kong Libraries .31 Baert et al..8. and thus the final pellet qualities. concluded that screen pressure was the most critical variable affecting the yield of 18/25 mesh cut pellets. http://dl. Schematic view of a ram extruder. and 5) extrusion temperature. The quantitative estimation of the screen pressure upon extrudability has been studied by various researchers.26 II.begellhouse. the ram extruder consists of a piston that pushes the wet mass through the screen situated at the end of the barrel (Fig. In addition.19. often with a minimum force at a certain level of filler. For a constant MCC/water ratio (50:50).27–31 In 1994.31. Conversely.33 The authors concluded that during the extrusion process.32 For this purpose. the authors found that the low substituted 283 Begell House Digital Library.4 mm or smaller was used for extrusion.27 For the same extrusion force.. the spheronization process. it was possible to obtain different performances. and a reduction of the extrusion pressure at the screen was necessary to prevent the screen from breaking. could not find a relationship between the extrusion forces required to extrudate the wet mass and the size of the pellets. and consequently the shape of the pellets. Kanbe et al. In light of the reduction of the screen pressure. it is necessary to run the extruder at a specific level of power consumption. however.43 by University of Hong Kong Libraries . the water content in the extrudate also differed and there was a wider size distribution of the pellets. Thus.34 A screen with a pore size of 0. Thus. and so forth. http://dl. 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. Kleinebudde et al.8. variations of the powder feed rate affected both the water content and the shape of the pellets.extrusion-spheronization: process Variables and characterization Boutell 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. Tomer et al. the authors concluded that there are some other factors that affect the size of pellets. investigated the effect of glycerol and surfactant (sodium lauryl sulfate and Pluronic F68) solutions on the extrusion force of MCC and barium sulfate. in the range studied.begellhouse. The screw speed did not have significant effects on the water content.com Downloaded 2010-12-13 from IP 147. reported on the feasibility of the manufacture of fine spherical granules by the extrusion-spheronization method.31. Due to changes in the extrusion force.15 Glycerol solution tended to increase the extrusion force. when different combinations of the ingredients with a single drug were used or when different drugs were used.32 The author also reported the influence of screw speed and powder feed rate on the required level of power consumption. the simple extrusion force measurements were insufficient to characterize the ability of the extrudate to spheronize. 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. whereas surfactant solutions decreased it. In a subsequent study. Kleinebudde reported that the power consumption-controlled extruder is an appropriate tool to adjust the extrusion force. screen pressure is directly dependent upon the amount of load.com Downloaded 2010-12-13 from IP 147.35–37 Baert et al. and carmellose calcium (ECG-505) markedly decreased the screen pressure.31 Gomez-Carracedo et al. and the variation in extrusion force affects the yield and size distribution of pellets. Similarly.8. 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.43 by University of Hong Kong Libraries . with a larger diameter in the perforations producing pellets with a larger diameter when processed under the same conditions.17 The authors found that the screen with low thickness formed a rough and loosely bound extrudate. used an extrusion screen with orifices of 400 µm in diameter and selected a formula that would pass through the small holes of the screen during extrusion.sinha et al.31. croscarmellose sodium (Ac-Di-Sol). A slight change in these parameters changes the screen pressure and thus the extrusion force. which is characterized by two parameters: the thickness of the screen and the diameter of the perforations. reported on the difference in extrudate quality by extrusion with different screen thicknesses. not the screen aperture size. amount of water used for granulation. Screen Hole Diameter Pellet quality is dependent on the extrusion screen.34 Thus. 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. the diameter of the perforations determines the size of the pellets. The dimension of the screen holes during extrusion is an important parameter that affects the final pellet properties. hydroxypropyl cellulose (L-HPC).begellhouse. surface morphology.18. composition of blend. The high swelling property of these excipients was closely related to screen pressure reduction. shape. and a few operational parameters such as the pore size of the screen and screw speed. and 284 Begell House Digital Library. http://dl. 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.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. 2.38 Dupont et al.14 Shah et al.39 and Bianchini and Vecchio40 have also studied the effect of extruder screen opening on the final pellet properties. especially the mean pellet diameter. the water content. depending on screw speed or. 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. more significantly. Batches that were extruded on the NICA unit showed a significantly lower bulk density than the Alexanderwerk or Gabler batches. and some food-grade extruders might not meet the Good Manufacturing Practices requirements. In some formulations. Forces of 1 to 5 bar were recorded.41 used four different types of extruders. consequently. Thoma et al. The selection of optimal screen size further depends upon the specific size requirements of the pellets based upon their application. sphericity and mean pellet size also differed significantly among the extruders. http://dl. the forces of extrusion were considerably larger than those of the radial screen extruders. The increase in surface smoothness of the extrudate with increase in water content of the formulations also differed in the Gabler unit.begellhouse.4 In addition.com Downloaded 2010-12-13 from IP 147.extrusion-spheronization: process Variables and characterization hardness. the type of extruder influences the extrudate quality and. . not all of the extruders are designed solely for pharmaceutical use. only a change in the water content is required when the 285 Begell House Digital Library. The selection of the extruder is critical because they are not interchangeable. Different types of extruders result in pellets exhibiting different characteristics. Extruder Type As described earlier.8. Thoma and Ziegler evaluated the difference in extrudate properties by using the different types of extruders mentioned above. the Gabler extruder failed to extrudate formulations containing more than 60% soluble ingredients such as lactose or mannitol. all of which required different amounts of water in their formulations.16 Due to an increase in the die length. many types of extruders have been used for the process of extrusion–spheronization. 3. Accordingly.4 Kleinebudde and Lindner described the instrumentation of a twin-screw axial screenmixer extruder.31.42 Unlike the others. which proved that the formulation could not be extruded successfully in the latter. whereas the Gabler axial single-screw extruder showed an almost unchanged pellet size over a wide range of water contents.43 by University of Hong Kong Libraries . Screen-type extruders induce minimum force. The NICA batches also exhibited a significant difference of the Hausner factor from the other two extruders. the pellet qualities. The output should be as high as possible for economical reasons. it is the powder feed rate to the extruder that affects both the water content and the shape of the pellets. but several authors18. In this case. such as roughness and “shark skinning. http://dl. The rise in temperature during the extrusion cycle could dramatically alter the moisture content of granules because of evaporation of the granulation liquid. the ram extruder would be a closer approximation. For example.17 In conclusion.43 by University of Hong Kong Libraries .8.45 state that an increase in the extrusion speed can influence the size and surface properties of the final pellets. 5. the use of 286 Begell House Digital Library.sinha et al. Screw Speed Screw speed of the extruder seems to have little effect on the final pellet qualities.com Downloaded 2010-12-13 from IP 147. Evaporation of water during extrusion is possible because most of the water is available as free water.19.” become more pronounced with increasing speed. The choice of extruder type also affects the density and thereby the Hausner ratio of the pellets. it would probably not be for an axial screw or gravity-fed extruder. found that although a small basket extruder would certainly be appropriate in combination with a paudal screen extruder. 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. extruder type is changed. resulting in a number of fines and a wide particle size distribution.44 The total output of the extruder is mainly governed by the extrusion speed.31.32. 4. 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.43 Baert et al. 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. Several studies show that the surface impairments. Extrusion temperature control becomes an important parameter when a formulation with a thermolabile drug is processed.begellhouse. Extrusion Temperature Extrusion temperature influences the pellet quality by affecting the moisture content. 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. To avoid a rise in temperature during an extrusion cycle. As early as 1972.6 They found that the pellets exhibited better roundness than the commercial nonpareil seeds and had excellent flow and packing properties.16. frictional plates with tear drop studs are used. more uniform and rounder pellets were obtained.43 by University of Hong Kong Libraries .extrusion-spheronization: process Variables and characterization a screw extruder with a cooling jacket around the barrel to keep the temperature of the given formulation between predetermined limits has been reported. the plate peripheral velocity can be calculated.47 Other characteristics. Woodruff and Nuessle reported that by increasing the speed of the plate.24 The edges of the grooves are required to facilitate the critical cutting of extrudates to form shorter and almost uniform-length segments. such as the diameter of the plate and its speed. In the case of drug layering with nonpareil seeds or coating with core spheroids.begellhouse.31. The plate design. however. plates with a smooth surface may be used.48 The surface of the friction plate used for extrusion-spheronization is grooved.4 All spheronizers have a smooth wall as part of their design. also have been found to show intense effects on the pellet qualities.com Downloaded 2010-12-13 from IP 147. and these data should be compared instead of the absolute rotational speed of the friction plate.49 Such grooved plates are the most appropriate for extrusion-spheronization. Lovgren and Lundberg observed that speed in combination with the diameter of the plate is important.8. differs and plays a very important role in the final quality of the spheroids. rather than the absolute speed of the friction plate. in which spheroids can be formed from powders in a single step. http://dl. where the groves form right angles. where the grooves form a radial pattern. 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.48 From these two parameters.20 III. 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.38 For rotary processing. and radial geometry. Two types of groove geometry exist: cross-hatch geometry.49–51 287 Begell House Digital Library.46 The basic design of all the spheronizers obtained from different manufacturers is similar. 5 mm were obtained from 1-mm extrudates.17 Due to the rotational and frictional forces involved in the spheronization process. defined surface area. 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.1 and equivalent diameters of approximately 1. Reitz and Kleinebudde reported that the spheronization of drugcontaining extrudates of Dynasan 114 and Witocan 42/44. starting from a cylinder over a cylinder with rounded edges. and Time Chapman et al.24 Another mechanism proposed by Baert and colleagues suggested that a twisting of the cylinder occurs after the formation of cylinders with rounded edges. The spheronization process was shown to be strongly temperature and formulation dependent. and concluded that the pellet size and porosity can be controlled by modifying the spheronization rate and spheronization 288 Begell House Digital Library. on the basis of a binary lipid mixture of hard fat and GTM. The material temperature during the process was influenced by the adjusted jacket temperature and friction and shear forces between the rounded particles. spherical pellets with low porosity. the edges of the flat side fold together like a flower. to dumbbells. and eventually to perfect spheres. to elliptical particles.sinha et al. Mechanism of Spheronization During the spheronization process. the cylinders obtained from extrusion are dumped onto the friction plate. each with a round and a flat side. Spheronization Operational Variables 1. According to Rowe. illustrated the effects of spheronization load and spheronization rate on mean pellet size and micropore volume using response surface methodology. forming the cavity observed in certain pellets.31.A.begellhouse.B. is feasible using a spheronizer without the addition of solvents.53 Alvarez et al. Spheronization Load. III. that is.com Downloaded 2010-12-13 from IP 147.43 by University of Hong Kong Libraries .5 Two mechanisms are proposed for the formation of the shears. http://dl. finally resulting in the breaking of the cylinder into two distinct parts. III. Speed. where the extrudate is broken up into small cylinders with a length equal to their diameter. and found that extremely small quantities provided insufficient plate-particle interactions. looked at the optimum pay load required for the preparation of the best-quality. and narrow particle size distribution with an aspect ratio of below 1.52 Under suitable process conditions.8. When larger spheronizer loads were used. http://dl.29 Maximum yield was achieved within 60 sec in 289 Begell House Digital Library. There were also a number of significant interactions between these variables.56 When spheronization time was increased. which reduced the water content necessary for the formation of good pellets.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. an increase in the spheronization load at a constant spheronization rate resulted in a decrease in both mean pellet size and micropore volume.54 In a factorial experiment. An increase in spheronizer speed increased the packing density because of the great compaction forces applied. the production of large pellets was high. Gouldson and Deasy evaluated the effects of spheronization load and spheronization time on pellet qualities. and sphericity index as a function of spheronization time. Increasing the spheronizer load increased the relative humidity of the spheronizer chamber during spheronization. Iyer et al.begellhouse. With small spheronization loads. sphericity.22 For both Avicel grades (PH 101 and PH 102) used in the study. and size of the pellets were increased. The smaller reduction in the pellet moisture level could be responsible for more spherical pellets.com Downloaded 2010-12-13 from IP 147. The influence of plate geometry on the size and shape of the pellets was studied by Schmidt and Kleinebudde (1998).extrusion-spheronization: process Variables and characterization load.47 Kleinebudde et al.8. which was found to increase with an increase in both spheronization rate and load.43 by University of Hong Kong Libraries . The shape was characterized by the circularity parameter as defined by Exner and Link.31. tapped density. With increasing spheronization time. At 800 rpm. The most spherical pellets were obtained when both factors were held at high levels. surface smoothness. found that the spheronization speed has an influence on the size but not on the porosity of the pellets. measured the percent yield. An increase in spheronization speed and spheronization load also resulted in an increase in the sphericity of the pellets. the yield of fines reduced significantly. the yield of large pellets increased with longer spheronization times.55 Sphericity also increased with an increase in the spheronizer speed. deterring further evaporation of water from the pellets into the chamber environment.21 The spheronizer plate with the rougher surface applied more mechanical energy to the extrudate and wet pellets. regardless of spheronization time. which was exacerbated by faster spheronization speeds. the production of large pellets was increased by increasing spheronization time when spheronized at 600 rpm. Both the mean pellet size and micropore volume change with a change in spheronization rate and spheronization load. 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.sinha et al.58 Both the drying temperature and the drying method can have profound effects on pellet properties. There is considerable interaction between spheronization time and spheronization.31.43 by University of Hong Kong Libraries . This pellet property was witnessed in the case of freeze-drying as well. and yield change with the change in spheronization time and spheronization load. it could be used as another ‘tool’ to modify pellet characteristics such as size. the spheronizer.com Downloaded 2010-12-13 from IP 147.8. quickly (microwave-drying or 290 Begell House Digital Library.58 The higher the temperature employed for drying. With small spheronization loads. indicating a shrinking process. density. circularity.60 Discussion about the incidence of drying on the properties of pellets usually only concern the speed at which the removal of water occurs—that is. the matrix structure remained intact in the majority of the pellets and shrinking reached the smallest value. the procedure for water removal may be of crucial importance to their microstructural properties. in fact.57 Bataille et al. The shape and density were found to be unchanged by increasing the residence time. and hardness.59 Because pellets densify further during the drying phase. the smaller the diameter. and almost all water content was evaporated in the first few minutes of the process.58 In this case. which increase with the increasing temperature. DRYING At the end of the spheronization process. the wet pellets must be dried4 to complete the formation of the matrix structure. Similarly. http://dl. the yield of large pellets increases with longer spheronization time. IV. whereas the yield was severely reduced.57 The drying step should not be considered as a secondary process. also studied the changes in pellet structure with different drying methods. and this can be exacerbated by faster spheronization speed. pellet size. drying was faster and uniform. There appears to be no shape change upon drying but diameter may vary. Microwave drying almost suppressed the shrinkage process. Pellet size and shape are highly influenced by the surface roughness of the spheronizer plate.begellhouse. The diameter findings are supported by the density determinations. consequently. Dissolution profiles were similar for tablets prepared using the oven-dried or the freeze-dried granules obtained by the process of extrusion-spheronization.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. http://dl. The curing process resulted in a significant decrease in the elastic modulus of the pellets.43 by University of Hong Kong Libraries . to a large extent. polyvinylphenol (PVP). and Eudragit RL PO pellets were prepared by extrusion spheronization. As a consequence. which was supported by differential scanning calorimetry (DSC) studies.64 The microstructural. the faster the entrance of water and. In another study done by the same researchers.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. for tablets compacted to the same final applied stress. 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.8. and mechanical properties can be modulated. the tablet surface was visibly smoother than that of the oven-dried counterparts.63 Gomez-Carracedo et al. The curing process also retarded drug release from pellets and increased mean dissolution time (MDT). It was shown that the cured pellets containing 40% or 60% drug exhibited a plastic deformation without any fracture under mechanical tests (Fig. Therefore. the faster the drug release. The pellets were cured in oven at 60oC for 24 h.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. the greater the pore size. consequently. 7).65 the slowly frozen pellets had the lowest porosity but the pores were larger. in which closed pores are predominant. the control of the ice formation is essential in modulating the release profiles.31. through the control of the drying step.begellhouse. 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. Pore size appears to be a critical factor for achieving controlled release. Eudragit RS PO. if freeze-drying is used to remove water from wet pellets. MCC. 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.extrusion-spheronization: process Variables and characterization freeze-drying) or slowly (oven-drying or desiccation on silica gel).com Downloaded 2010-12-13 from IP 147. morphological.66 291 Begell House Digital Library. begellhouse. Scanning electron micrograph of the surface of a pellet containing 60% ibuprofen before curing (A) and after curing (B). INFLUENCE OF MOISTURE ON EXTRUSION-SPHERONIZATION Pellet preparation by extrusion-spheronization is impossible without the presence of a suitable granulating fluid. 67/ed.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. Abbaspour MR. and Garekani HA. 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. the pellet quality improves on increasing the percentage of water in an ethanol/water mixture.3. Thermal treating as a tool to produce plastic pellets based on Eudragit RS PO and RL PO aimed for tableting. FIGURE 7. vol. 1. V.68 In addition. the presence of water as a granulating fluid is the most important formulation requirement. 260–7. Sadeghi F. these factors should be chosen on the basis of composition of blend and the desired drug release from the pellets. with permission from Elsevier. Copyright © 2007.67 To spheronize MCC. even in very small quantities. 292 Begell House Digital Library. Reprinted from the European Journal of Pharmaceutics and Biopharmaceutics. pp.43 by University of Hong Kong Libraries .4 MCC is the most widely used excipient in extrusionspheronization.8.31. http://dl.com Downloaded 2010-12-13 from IP 147.sinha et al. Therefore. bulk. Water contents of around 35–40% (w/w) produced pellets of the highest bulk and tapped densities. friability index.8. Elbers et al. Pellets were less friable when the water content was higher. The variation of water content in the formulation can also occur during both the extrusion and spheronization stages.43 by University of Hong Kong Libraries .70 They reported that mean size. and tapped densities — varied with the amount of water used during the process. indirectly. increased linearly with the amount of water added for all of the 11 MCC grades studied. 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.71–75 2) mixer torque rheometry. The water 293 Begell House Digital Library. Beyond this. flow rate. is very important in governing pellet quality. At water contents of 40% (w/w) and above.A. as higher water content ensured that there was more lactose in the dissolved form (used in the formulation). the water content).31.26. as determined by logarithmic geometry. and many studies have focused on this aspect of the process.77 and 4) controlled stress rheometry.78.80 quantified the plasticity of formulations using an apparatus originally reported by Alleva and Schwartz. http://dl.com Downloaded 2010-12-13 from IP 147. Evaluation of Rheological Properties of Wet Powder Mass Many methods have been used to evaluate the rheological properties of wet powder masses (and. friability indices of pellets produced from different MCC grades did not differ significantly compared with those produced at lower water contents. which can be correlated with the increase in pellet size accompanying the increase in water content: larger pellets cannot flow through orifices as easily.begellhouse.extrusion-spheronization: process Variables and characterization Water content of the formulation. both before and after extrusionspheronization. V.79 Plasticity measurement of the drug excipient mixture is another parameter.69 Heng and Koo concluded that all of the essential qualities of pellets — such as pellet size.76 3) powder rheometry. The reason for this was ascribed to the formation of a solid bridge upon drying. The flow rate decreased with increasing water content. which can be correlated to the type and amount of granulating liquid used.81 and characterized their behavior with respect to the type and amount of granulation fluid. These include: 1) capillary rheometry.8. Pellets produced using 45% (w/w) water content were too large for flow measurements. an increase in water content produced bigger pellets that packed less well and showed lower densities. 8. Extrudate is brittle in this low state of saturation and will shatter. V.B.83 In such cases.67.15 There will also be a wider size distribution.79 During spheronization. MCC showed a slow but continuous removal of water compared to the bed of barium sulfate alone. due to capillary suction.sinha et al. more water was removed.43 by University of Hong Kong Libraries .begellhouse. then the liquid distribution within it is also higher.31. as the extrudate will vary in water content.86–88 3) NMR imaging. which tends to increase the deformability of moist aggregates (for example.15 As the pressure was increased. the liquid from inside will move to the surface. resulting in a large yield of fines. resulting in agglomeration of the pellets. http://dl. because excessive pressure is required to consolidate the material to remove the air voids. a lot of dust will be formed during spheronization. and 2) forcing the wet mass along the die.82 Satisfactory extrusion of such dry systems is unlikely. If the amount of liquid in the granulation is higher. the centrifugal force induced by the rotation of the plate can cause water to migrate to the surface.15.87–89 Boutell et al. movement in the mixture depends on both the formulation and the applied stress. 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.88 and 4) the centrifuge technique. Agglomeration can occur if the surface of the half-formed pellets bed is too wet during spheronization. generating a large quantity of fines when broken up on spheronization and having insufficient plasticity to form spheres. and a 1:1 mixture of the two at various applied pressures.84 and may be increased by any means.87. the mixture behaved 294 Begell House Digital Library. Agglomeration may also occur by coalescence. which results in agglomeration. quantified the volume of liquid movement through a bed of MCC. barium sulfate. by reducing their tensile strength and/or by improving their plastic deformation). There are two stages of extrusion that can induce water movement: 1) forcing of the mass from a large diameter into the die.com Downloaded 2010-12-13 from IP 147.85 2) subjecting a wet mass to extrusion through a die and evaluating the variation in water content of the extrudate. When the two excipients were mixed in equal proportions. If the moisture content is less than the lower limit. 90 As the percentage of barium sulfate increased to 80%. Prieto et al. Unlike microcrystalline cellulose mixtures (in which the optimal amount of wetting agent for extrusion-spheronization is that giving maximum torque). have shown that the amount of water required to prepare a proper wet mass is affected by the composition of the formulations.31. because it produced a greater percentage of granules within that size fraction at all time points. significant moisture content was required.43 by University of Hong Kong Libraries . the extrudate containing coarse lactose appeared to be more plastic than the fine lactose extrudate. The lower the surface tension and the contact angle. the optimal amount of wetting agent was more accurately predicted by maximum torque amplitude. With an increase in the percentage of barium sulfate in the mixture with MCC. Fielden et al. the quantity of water required also increased to produce a consistent product in terms of size.92 Torque rheometry was used to characterize the rheology of wetted masses of the different excipients and excipient mixtures.91 The required amount of water decreased with increasing drug load and percent of PVP. there was considerably more water removal from the bed of MCC. The water requirement for formulations containing fine lactose particles was relatively wide as compared with those containing coarse lactose particles. 295 Begell House Digital Library. characterized the different excipients in terms of morphometry and basic physical properties. 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.begellhouse. the optimal amount of wetting agent for the starch and starch-dextrin mixtures tested in this study was lower than that giving maximum torque. The authors also evaluated the water absorption and water retention capacities of each excipient. At the same moisture content. http://dl. with the aim of determining the optimal amount of wetting agent (water). the greater the water removal.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. In fact. When surfactants were added. Abbaspour et al.8. found that the particle size of lactose in pellets containing MCC and lactose influenced the appropriate amount of moisture content required for successful pelletization.extrusion-spheronization: process Variables and characterization more like MCC than barium sulfate. These authors also showed that formulations containing Eudragit RL require more water.com Downloaded 2010-12-13 from IP 147. 93 Long.43 by University of Hong Kong Libraries . http://dl. Scanning electron micrograph showing the effect of the granulating liquid on the shape. has been assessed.begellhouse. Reprinted from the European Journal of Pharmaceutics and Biopharmaceutics. and Puttipipatkhachorn S.93 Sriamornsak et al. 227–35. Nunthanid J. FIGURE 8. dumbbell-shaped pellets were obtained with viscous granulating liquids. 1. short. and high (ascorbic acid) water solubility. intermediate (lactose). (A) 10% PVP in 5% ethanol and (B) 3% calcium chloride solution. 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). size. 8). vol. pp.com Downloaded 2010-12-13 from IP 147. 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. However. with permission from Elsevier. The two new types of MCC (B 6 and B 8) were able to form goodquality pellets with all three model drugs. 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. Copyright © 2007. 67/ed.sinha et al. Luangtana-anan M.8.31. nearly spherical pellets were obtained with watery granulation liquids with calcium chloride that reduced the swelling ability of sodium alginate (Fig. 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. investigated the effect of additives in granulating liquid on sphericity of pellets prepared by extrusion-spheronization. Sriamornsak P. whereas Avicel PH 101 296 Begell House Digital Library. and size distribution of alginate pellets. Alginate-based pellets prepared by extrusion/spheronization: A preliminary study on the effect of additive in granulating liquid. FORMULATION VARIABLES Formulation aids or excipients are added to pharmaceutical dosage forms mainly to produce satisfactory delivery of the drug to the intended site.37.96 It has been proposed that MCC adds to the tensile strength of the wet mass through autoadhesion (the interdiffusion of free cellulose polymer chains). VI. and nondisintegrating upon extrusion-spheronization. http://dl.43 by University of Hong Kong Libraries .97 297 Begell House Digital Library.8. size. but also influence the growth mechanisms of the pellets manufactured by the various processes.com Downloaded 2010-12-13 from IP 147. Consequently.95 Examples of excipients that are commonly used during the manufacture of pellets are given in Table 2. Microcrystalline Cellulose Microcrystalline cellulose has been studied extensively as an extrusion-spheronization aid. The presence of a binder also affects the amount and type of granulating fluid required. The excipients not only affect the interplay between physical and mechanical forces during pellet formation.95 Avicel PH 101 has come to be regarded as an essential formulation component for successful extrusionspheronization. pellet hardness. to impart favorable characteristics to the dosage forms.94 Thus. friability.A. 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. 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.extrusion-spheronization: process Variables and characterization could not form pellets with this high level of ibuprofen. noncompressible. and to facilitate the manufacture of the product. shape.begellhouse. VI. Kleinebudde has proposed a “crystallite-gel” model. the amount and type of wetting agent employed as the granulating liquid are highly dependent upon the composition of the powder blend.31.4. It is autoadhesion that makes pellets composed of neat MCC hard.96 To explain the process of the production of pellets by extrusionspheronization. Thus. and dissolution characteristics depend largely on the properties of the excipients used. 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. TABLE 2.31.95 298 Begell House Digital Library.8.begellhouse.sinha et al.com Downloaded 2010-12-13 from IP 147. 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.43 by University of Hong Kong Libraries . http://dl. shape. The above-mentioned models may hold true in some cases but not in others. which may be related to its smaller particle size with fewer aggregates. and volume in the finished product compared with the original MCC powder. compared Avicel PH 101 and Pharmacel 101. improved flow. lower 299 Begell House Digital Library. Based on these results.9. and it is the gel network that aids both extrusion and spheronization. each particle of MCC would behave as a porous sponge and each particle would be able to absorb a large quantity of water.31. MCC particles are broken down into smaller particles and possibly ultimately single crystallites in the presence of water. The degree of polymerization (DP) of MCC and other cellulose materials also influence the extrusion-spheronization process.99 Coating the pellets.com Downloaded 2010-12-13 from IP 147. During the extrusion process.100 MCC void volume and packing properties play an important role in determining water retention and release during extrusion-spheronization.98 Under pressure. and should be of the same size. whereas the gel model is more applicable to cellulose types with lower DP (MCC). the pellet qualities. 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. While it is well established that MCC has unique properties as an extrusion aid. using other ingredients in the pellet formulation.begellhouse. According to the “sponge” model.70 This property dictates to a large extent the water requirement of the MCC grade and. and found that Avicel PH 101 was superior.8. it was postulated that the sponge model is more appropriate for the cellulose type with high DP (powdered cellulose). the water would be partly squeezed out but could be taken up again after releasing the pressure while the volume increases. 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.33 Cellulose types with a high degree of polymerization value showed greater pellet size after homogenization than the types with a low DP value. http://dl. it is proposed that during granulation and extrusion. there is no model that would sufficiently explain its specific role. When mixtures of drug and MCC are extruded and spheronized. or both can further control drug release. Colloidal sizes form a gel.43 by University of Hong Kong Libraries . the MCC acts as a matrix from which the drug can slowly dissolve.extrusion-spheronization: process Variables and characterization In this model. MCC particles remain intact during the processes of wet-granulation and extrusionspheronization.44 Law et al. subsequently. Thus. the spheroid qualities are less sensitive to water content as the proportion of Avicel PH 101 is increased in the mixture. to possess a narrow size distribution. at lower water contents. The pellets prepared from MCC usually do not disintegrate. MCC packing and void volumes play a role in determining pellet-packing densities.103 Some control over pellet porosity can be exerted by the selection of the cellulose grade used. largely due to the favorable plastic rheological characteristics of the MCC/drug/water pastes that are formed. Koo and Heng reported that with an increase in the density of MCC grade used. http://dl.sinha et al.com Downloaded 2010-12-13 from IP 147. spheronization speed. However. It has been shown that MCC can be formed into spheroids over a wide range of drug:MCC ratios. Although MCC is the most widely used excipient in extrusionspheronization. produced the best pellets. and therefore produced pellets that more readily retained their desired size range.21. MCC grades with high packing densities produced pellets of higher bulk and tapped densities at lower water contents.43 by University of Hong Kong Libraries . leading to diminished drug 300 Begell House Digital Library. and to display good release characteristics for active drugs.begellhouse.22 Pellets prepared with Avicel of larger particle size had higher porosities than those prepared with Avicel of smaller particle sizes. MCC is also less adversely affected by variations in added water. it does have some limitations. A higher yield of undesired large pellets and a wider range of sizes were obtained with Pharmacel compared with Avicel over similar experimental conditions. and drying time and method — were kept constant. and showed that higher grades of MCC used. extrusion speed and temperature.22. the type of extruder. the sphericity of the pellets decreased owing to more resistance of the MCC toward the forming and shaping forces involved during the spheronization process.101 Avicel also appeared to be less sensitive to minor variations in moisture content likely to be encountered in use.21.103 MCC grades with higher tapped densities produced pellets showing poorer flow properties. studied a range of MCC grades. the influence of MCC-tapped densities on packing properties of the pellets diminishes as pellets become larger.104 (since those early studies) to be dense and spherical.101. such as Avicel PH 101.102 Different grades of MCC show different extrusion-spheronization behaviors.70.8.103 Variables that may influence the quality of the final pellets — including the type and concentration of binder. as pellet size increases with higher water content.31. Sinha et al. and absence of traces of cellulose II in its cellulose I content. depolymerization temperature range. Pellets formed with MCC have been proven many times37. although with different types of formulation parameters. various other polymers have also been used to facilitate pellet formation by extrusion-spheronization. MCC.109 Owing to these drawbacks.31. and hydroxypropylmethylcellulose (HPMC) acetate. http://dl. Both of the pellets were suitable enough to be used as controlled-release carriers. In pellets containing Carbopol and MCC. which poses a limitation for moisture-sensitive drugs. Kojima and Nakagami did not use MCC for the preparation of pellets and carried out extrusion-spheronization by subsequent annealing with water-insoluble polymers. a water-soluble drug. the mean pellet diameter was influenced by the ratio of the two ingredients in the blend. prepared pellets of gelucires by extrusion-spheronization. and any one of these can be used depending upon the requirements in regard to such factors as size. especially for poorly soluble drugs. Avicel PH 101 is the most commonly preferred among the various grades of MCC used in extrusion-spheronization. Eudragit 4135F.100.114 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. reported stability issues of ranitidine with MCC when used in excess of 60%. Pellet properties vary by using different grades of MCC.39 Neau et al. used Carbopol as a release-modifying agent in pellets containing MCC.106 Basit et al. and PEG 8000 were used for the preparation of pellets by extrusion-spheronization.113 A hydrophobic gelucire type (50/02) and a hydrophilic type (55/18) were used to sustain the release of theophylline. which leads to reduced porosity and thereby hinders entry of the dissolution medium into the pellets. shape. Castor oil and ethanol were used as the wetting fluids.100 301 Begell House Digital Library.extrusion-spheronization: process Variables and characterization release. The hydrophilic gelucire produced good-quality spheroids.110 Triethyl citrate was used as the plasticizer. as they cannot be interchanged.107 The presence of water is essential for formulating spheroids using MCC. and drug release.com Downloaded 2010-12-13 from IP 147.43 by University of Hong Kong Libraries . Other Types of Excipients In addition to MCC.B.8. along with theophylline. various other excipients have been used in the process of extrusion-spheronization. whereas Avicel had to be added to the granulation matrix to produce the hydrophobic type of pellets.begellhouse. VI.110–112 Montousse et al.108 Water content needs to be optimized with different grades of MCC.105 Slow dissolution of the pellets formulated with MCC has also been attributed to the pronounced contraction of the pellets during the drying phase. ethylcellulose. Charoenthai et 302 Begell House Digital Library. favoring maximum yield of highest-quality pellets. and wetting agents such as sodium lauryl sulfate improved sphericity but reduced yield due to agglomeration. An increase of plain β-cyclodextrin content in granules reduced granule size. SCMC. The mass fraction of chitosan within the pellets could be increased to 100% by using diluted acetic acid for the granulation step.119 The authors concluded that by using demineralized water as the granulation fluid. and tartaric acid also promoted the production of oversized pellets. prepared the complex of triamcinolone with β-cyclodextrin to incorporate more than 90% of the drug in the pellets.115 However. HPC and PVP were the most satisfactory because they had the least adhesive strength.102 Among the various silicates examined. The use of β-cyclodextrin.116 Villar-Lopez et al.117 Otherwise. or PVP aided the process of extrusion-spheronization of MCC.com Downloaded 2010-12-13 from IP 147. Bentonite.31. also produced satisfactory pellets.sinha et al. It was also found that a high amount of Carbopol in the blend resulted in the highest-quality pellets.begellhouse. The complex formation procedure increased the proportion of triamcinolone released by the 15:80 (MCC:β-cyclodextrin) formulation from 49% to 53% in spite of a parallel increase in granule diameter from 638 to 1042 µm. Likewise. wherein chitosan was expected to be dissolved. HPC. Weak bases such as sodium bicarbonate and weak acids such as fumaric acid also aided spheronization. Steckel and Mindermann-Nogly demonstrated that the chitosan pellets using MCC (0–70% w/w) as an additive could be prepared by extrusion-spheronization using diluted acetic acid solution as the granulating liquid. http://dl. Kaolin.8. HPMC. among these. Waxy materials such as hydrogenated caster oil and Precirol ATO 5. resulting in a gel-like wet mass. a model mixture of MCC and lactose wetted with water. citric acid.43 by University of Hong Kong Libraries . more than 80% β-cyclodextrin in the formulation resulted in unextrudable pastes even at lower water contents.118 They found that spherical pellets could be obtained by using ethanol as the granulating liquid. even at a content of 90% w/w. Law and Deasy examined the different classes of excipients for extrusion-spheronization. pellets with a maximum of 50% w/w chitosan could be produced. and Veegum F provided improved plasticity for the formation of spherical pellets. Increasing the content of Carbopol in the formulation resulted in a significant reduction of the percentage of drug released. talcum. Tho and coworkers produced pellets from pectin by extrusionspheronization and identified factors influencing the process and the characteristics of the resulting product. was the same and is considerably less than that required with MCC alone.43 by University of Hong Kong Libraries . as absorption enhancers) perform in the same way? To investigate these issues. 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.123 As a comparison. For three different types of glycerides. do these allowable differences change the performance of the products. have shown that it is possible to incorporate the glyceride. and water.25–2.5% w/w sodium alginate was included in the formulations with no MCC. grinding. 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. the water level required to provide smooth regular extrudate at equivalent extrusion forces.com Downloaded 2010-12-13 from IP 147. even the Japanese Pharmacopoeia (JP). The replacement of the GMS with Imwitor 742 allowed an even further reduction in the quantity of water required for pellet formation. The presence of GMS did not influence this effect.31. which may have implications for the stability of some drugs. pharmaceutically acceptable glycerides provide an additional option when it comes to the formulation of pellets by extrusion-spheronization. which readily form spherical pellets. a formulation containing 10% drug with 90% MCC was reported as a standard. Such systems retained the processing characteristics of 303 Begell House Digital Library. MCC (60%). Newton et al.120 Thommes and Kleinebudde proposed the use of k-carrageenan as an alternative pelletization aid to MCC in the extrusion-spheronization process.8.121 Chatchawalsaisin et al. It was also possible to prepare the pellet formulations by dispersing the drugs in molten GMS. used a previously reported successful formulation that contained a model drug (10% diclofenac sodium) with a range of glycerides as an additive (30%). and the United States Pharmacopeia–National Formulary (USP–NF) differ in their standards. into pellet formulations at a level of at least 30% and still produce round pellets without reducing the in vitro drug release. The question arises. therefore.122 The formulations required less water than those containing MCC alone as the spheronization aid.extrusion-spheronization: process Variables and characterization al. Thus. glyceryl monostearate (GMS).begellhouse. European Pharmacopoeia (EP). reported that the spherical pellets with a maximum fraction of 60% w/w chitosan could be produced when 1.g.. GMS is not a pure material. and would other types of glycerides used in pharmaceutical formulations (e. http://dl. and processing this with MCC and water. evaluated the possible use of starch and agglutinant mixtures as principal excipients for extrusion-spheronization pellets. The steady state. The extrudate diameter was found to increase with the quantity of GMS in the formulation. and density were also determined.31. 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 presence of GMS reduced the quantity of water required for the process to function.20) were obtained.127 304 Begell House Digital Library. roundness.sinha et al.126 Sriamornsak et al.com Downloaded 2010-12-13 from IP 147. bead average diameter.43 by University of Hong Kong Libraries . investigated the possibility of producing two types of sodium alginate-based pellets by a basket extruder.92 Their results showed that starch (corn or wheat) plus 20% white dextrin yielded high-quality pellets with good size and shape distributions. This approach incorporates minimal processing aids. Bommareddy et al. Chatchawalsaisin et al.begellhouse.122 Prieto 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. In addition to the drug release profiles. The surface of the extrudate appeared smooth and of narrow size range. or the mean of the range of the forces observed during forced flow.124 They confirmed that this ionic interaction with the drug affects the behavior of the wetted Carbopol. taking advantage of the properties of soluble polyethylene oxide (PEO) and methoxypolyethylene glycol (MPEG).125 The formulation consists only of water-soluble components. was dependent on the composition and the quantity of water added. Immediate-release bead product with a high yield (greater than 60% of 1-mm diameter beads) and low friability (mass loss less than 4. 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. the composition made by the blending of the powder.8. Howard et al. friability. http://dl.0%) that were spherical to the naked eye (roundness score less than 1. The success of this approach has important implications in cases in which high-drug-load beads are desired. presented a means to produce extruded-spheronized beads devoid of MCC and with a high drug load (greater than 80% w/w). 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. but MCC cannot be used due to chemical incompatibility or complete release cannot be achieved with MCC-containing beads. com Downloaded 2010-12-13 from IP 147. Soluble constituents may also crystallize and contribute to the bonding mechanisms. HPC-L. The best formulation contained Elcema P 100 with 1% binder.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. MCC and dicalcium phosphate dihydrate.56 Pellets using HPC-M as a binder at high spheronizer speeds showed spherical shape.begellhouse. and drug release behavior.3%. However. shape. Binders The selection of a suitable binder and its concentration is a critical formulation variable during pelletization. the precipitation and hardening of the binder takes over as the main bonding force. 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. Initially. Rodriguez et al.129 Likewise. http://dl.extrusion-spheronization: process Variables and characterization Different sodium alginate types responded to shape modifications to a different extent. and Methocel A4M. and good flow properties compared with Methocel E15LV. 3%. increased with the addition of binders (gelatin and methacrylic polymer). different types of sodium alginate and calcium salt responded to modifications to a different extent.31. and 10% w/w) on pellet properties such as size.e.8. This phenomenon was due to a change in the particle bonding of the pellets at concentrations of 40% 2-propanol. however. The analysis of the pore system in terms of fractal 305 Begell House Digital Library.. Sriamornsak et al. narrow size distribution. During wet massing for extrusion or granulating.43 by University of Hong Kong Libraries .128 The results showed that the amounts of sodium alginate and calcium salts influenced the size and shape of the obtained pellets. evaluated the effects of amount (i. as the liquid evaporates. 10–50% w/w) and type of sodium alginate and the addition of either calcium acetate or calcium carbonate (0%. VI. 0.95 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. found that porosity deviation of pellets prepared with two diluents. the binder is usually added as a liquid. an increase in binder concentration increased the particle size. morphology.44 The formulations appeared to be equivalent in terms of extrusion performance but differed in spheronization. it is the liquid bridges that hold the particles together. The structure of pellets can be markedly influenced by the composition of the granulation liquid.C. The use of an excess amount of binder gave rod-shaped pellets. predicted the drug solubility effects on the quality of pellets.43 by University of Hong Kong Libraries . however.130 Increasing the volume of binder solution increased the mean size of the pellets but decreased the yield in the desirable pellet size range. and water-insoluble drugs are easier to spheronize than water-soluble drugs.39 Generally. the water content range over which quality pellets could be produced was much 306 Begell House Digital Library.131. 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.68 MCC could not be processed into pellets using absolute alcohol. whereas the 95% ethanol granulated pellet formulations were reasonably compressible.28.132 The presence or absence of drug was important in influencing the mean diameter of the pellets.4 A quantitative relationship was identified between the quantity of pellets in the 1–1. VI.4 mm size range and the solubility of the drug. water-granulated MCC containing formulae resulted in strongly bonded. 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. Sriamornsak et al. For poorly soluble drugs. formulations that contain a low proportion of drug are easy to spheronize. When lower amounts of binder solution were used. dimensions implied a dependency of the fraction of 2-propanol in the granulation liquid on the pore structure.8. Influence of Drug Apart from the properties of the excipients.D. showed that the type and concentration of binder affected the appearance of the resulting pellets.sinha et al. Likewise.com Downloaded 2010-12-13 from IP 147. pellets with lower strength and less uniform shape did result as the level of ethanol in an ethanol/water granulating fluid increased.31.131 A strong linear relationship was observed between the aqueous solubility of the drug and the water content required for optimum pellet formation. http://dl. the selection of a suitable binder and granulating liquid and their concentration is required for consideration in pilot scale-up studies.begellhouse. hard pellets with good shape. The difference in bonding strength due to water or ethanol was also shown by the fact that pellets with pure water exhibited less compressibility. The type and concentration of binder plays an important role in pellet properties alone and/or in combination with the granulating liquid.28 Hileman et al. therefore. spherical pellets were not obtained. ” indicating the possibility of water migration during the process of ram extrusion. 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.124 Caffeine was released faster than chlorpheniramine maleate from these beads.133 Using cluster analysis. The particle size of the drug also influences the pellet properties. water movement within the formulation increased. The drug D also required consistently less water to function than the other three drugs. diclofenac sodium (D). the release of different actives from Carbopolcontaining beads was compared.27. Lustig et al. showed that as the particle size of the model drug increased.8.extrusion-spheronization: process Variables and characterization broader. From this observation.134 Like Tomer et al. The drugs differed in their response to extrusion in that all formulations containing the drug D had a “steady-state” extrusion profile. and indomethacin (IN) — at a 10% level with and without the addition of a range of levels of glyceryl monostearate (GMS). studied 20 model drugs at a level of 80%. although chlorphe- 307 Begell House Digital Library. whereas the other three drugs exhibited “forced flow.. The presence of GMS did not influence this effect. and a best level of water was identified for each drug.27 The processability and properties of pellets containing five different drugs of similar chemical structures also showed significant variance.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. They also could not find any relationship between solubility of the drug and pellet qualities.31. for a series of model drugs mixed with equal parts of MCC. in all cases pellets could be produced. which may have been due to the high percentage of drug used. ibuprofen (IB). indicated that the level of water and type of model drug were the most significant factors in determining the particle size.122 In another study. http://dl. Jover and colleagues also could not find any satisfactory relationship between the drug properties such as pKa and freezing point depression and pellet properties. resulting in a tendency of the pellets to agglomerate on the plate. Tomer et al. Fielden et al.43 Pellets have been prepared by extrusion-spheronization containing MCC and four model drugs with decreasing order of solubility — paracetamol (P).begellhouse. demonstrated that.134 Jover et al. it appears that numerous unidentified factors are also involved in the production of satisfactory pellets.com Downloaded 2010-12-13 from IP 147. the authors concluded that the prediction of satisfactory pellet formation from drugs with similar chemical structures was not possible.43 by University of Hong Kong Libraries . VII.8. Pellet quality is also affected by the type and amount of excipients used with regard to the drug used for pellitization. but the ruggedness was not affected. 308 Begell House Digital Library. caffeine and dyphylline. density. shape. 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. 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. niramine maleate is more soluble (160 mg/mL) than caffeine (20 mg/ mL). which are discussed below. which have been shown to be dependent on the chemical nature of different types (free-base.begellhouse. roundness. 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. Release profiles for the two salt forms were nearly superimposable. and flow properties. even before the swelling and gelling of Carbopol was visually observed. shape release. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation were contributing factors to the release mechanism in each case. In light of these results. were released at approximately the same rate. and yield of the pellets. The nonelectrolytes in the study. friability. Paker-Leggs and Neau examined the drug release rates from extruded-spheronized beads containing Carbopol.com Downloaded 2010-12-13 from IP 147.135 Different forms of model drug resulted in different bead average diameter. although polymer relaxation was more influential with the free-base form.31. although the solubility of dyphylline (333 mg/ mL) is substantially higher than that of caffeine. hydrochloride. but the free-base form was released more slowly. size. http://dl. and smoothness.sinha et al. porosity.43 by University of Hong Kong Libraries . and maleate forms) of drugs. EVALUATION OF FINAL PELLET QUALITY The pellets formed by extrusion-spheronization are evaluated by various parameters such as size distribution. 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. com Downloaded 2010-12-13 from IP 147. speed. and temperature. Podczeck et al.58 The size of the pellets is also dependent on the formulation parameters. spheronization time and speed.8.21.extrusion-spheronization: process Variables and characterization VII.B. the smaller the diameter.11. The process variables that affect the particle size are the extrusion screen. When the extrusion screen of a small mean hole diameter was used.43 To produce pellets of equivalent size. VII. binder type and its concentration. especially on moisture content and the type and amount of binder employed during granulation.55 The effect on the mean pellet size due to plate geometry has also been studied. and time on mean pellet size. http://dl.begellhouse.C.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.A.58 In addition.14 Mean particle size also varied according to the type of extruder used. Various studies have investigated the effect of spheronization load. which raises an important issue of how to assess this important 309 Begell House Digital Library. determined the Feret diameter. a ram extruder required different water content than a gravity-fed extruder. The various formulation variables reported to influence the pellet properties are moisture content. 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. and excipients.22.21. 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. the longest diameter and projected area (A) from the pellet images.29. The higher the temperature employed for drying.47 Mean size of the pellets is also influenced significantly at the last stage of spheronization: drying. which was discussed in Section VI.31. the pellets were larger when they were freeze-dried57 or dried in a microwave oven.43 by University of Hong Kong Libraries . small pellets were obtained. Sphericity One of the most important characteristics of pellets is their sphericity. drying technique. A perfect sphere will have PS = 1.22 It is generally performed by using sieve shaker with a series of standard sieves. 31. there is no exact number applicable to distinguish between spherical. were computed using the formulae given below. Surface texture distribution and shape. The two parameters. square. 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. This is a complex issue.8. the aspect ratio and the pellet circularity. A visual record of the change in granule shape was obtained by taking high-speed photographs of the spheronization.138 The distribution of the geometric shapes and surface irregularities of particles139 and soil granules can be related to their application properties.137 The method is based on determining the center of gravity of the particle from a digitized image of the coordinates of its outline.140 However. a circle. respectively. where A and P stand for the projected area and the perimeter of the pellet. 310 Begell House Digital Library.4 This method does not consider the aspects of surface texture of the objects.48 which they related to an overall proportion to represent the sphericity of the pellets. parameter. 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). as recorded using the software from the digitalized image.sinha et al.begellhouse. can be characterized using fractal geometry.0. or other polygonally symmetric shape will have an aspect ratio of 1. and perimeter of core pellets are usually investigated by optical microscopy image analysis. however.82 However. Lovgren and Lundberg proposed the concept of aspect ratio. and computing the angle necessary to incline a plane such that the center of gravity moves outside the boundary of the particle.com Downloaded 2010-12-13 from IP 147. which is the ratio of the longest to the shortest dimension of the particles. http://dl. Chapman et al. for fractals. aspect ratio. because in these examples. However. polygonal. or unorganized particles. this method did not provide any quantitative estimation of the spheroid sphericity.4 The shape. area.43 by University of Hong Kong Libraries . the length and breadth are equal. and many publications that claim to deal with a spheronizing process fail to provide a quantitative answer to validate their claims. eR.31. This value also differentiates between different polygonally symmetric figures. Pm is the measured perimeter of the particle.com Downloaded 2010-12-13 from IP 147. A roundness value of 1. Koo and Heng used a simple technique to describe the shape of pellets using the following formulae103: Using the above formulae.43 by University of Hong Kong Libraries . eR is able to detect small deviations from circularity and differentiates between more or less elliptical figures. the overall shape of any particle can be characterized and quantitated. 311 Begell House Digital Library. http://dl.extrusion-spheronization: process Variables and characterization Podczeck and Newton developed a shape factor. Neau et al. and b is the breadth of the particle.8. The factor 0.begellhouse. 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. based on the deviation of shape from a circle toward an ellipse and surface irregularities141: where re is the average radius of the particle.0 corresponds to the image of a perfect sphere.9399 corrects the perimeter for the effect of the corners produced by digitization of the image. even when the aspect ratio provides equal values. and higher values correspond to less spherical images. l is the length of the particle. begellhouse.31. In the truest sense. The basic principle of measuring the granule strength is more or less similar to the measurement of the compression strength.8. If pellets are to be compacted. The material is again shaken on a screen of that particular mesh size.sinha et al. the drying temperature of the prepared pellets. 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.70 the excipient used. The amount and type of binder used in the granulation also affect the granule strength. wi is the initial weight of granules before friability testing. 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. The granules are then placed in a container that is tumbled or shaken for a predetermined time with or without additional attrition. unfortunately. However. it would appear that smaller granules are more poorly formed and less robust than their larger counterparts. VII. Therefore.43 by University of Hong Kong Libraries . Image analyzers and specially designed computer programs are needed to calculate the data to arrive at a statistically significant conclusion.C. a granule is placed between anvils and the force required to break the granule is measured. from which only the circularity can be estimated. Other factors include the moisture content.com Downloaded 2010-12-13 from IP 147. all of the image analyzers take only two-dimensional images of the objects. and wr is the weight of granules retained above the sieve after friability testing. Larger granules may possess greater strength than the smaller ones142. http://dl.142 In this test. 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. all of the methods described above give only an estimation of the roundness or circularity of the pellets and not their sphericity. Friability and Granule Strength There are various factors that may affect granule strength.58 and the type of base plate in a rotary spheronization process. 312 Begell House Digital Library. Friability determination typically involves taking granules that are known to be greater than a particular mesh size.58 the drying method of the prepared pellets. when Lindner and Kleinebudde used the method reported by Korber and Moest. their weight. P is the strength when the granule broke. dissolved substances in the pellets may migrate to the surface and form a crust that 313 Begell House Digital Library. linear strain.31. For the same batch of granules. even as the former found a significant decrease in percentage friability by increase in binder concentration. ethanol.58 Similarly.56 For the determination of granule strength. which does not facilitate the comparison of all the results. whereas the effect of the coating material was not significant with respect to the elastic modulus.8. Analysis of variance established a significant increase in the strength of the soft GMS. Using the process of extrusion-spheronization.56 The dimension of the balls. The large variation in the data did not allow a model to be fitted.1%. Lindner and Kleinebudde found that for the same batch of pellets.com Downloaded 2010-12-13 from IP 147. as water evaporates.begellhouse. designed MCC pellets to vary their mechanical properties by the incorporation of lactose.. or glycerol. The authors demonstrated that the coating film affected the mechanical properties of the pellets differently depending on the properties of the core pellets.144 the friability values were below 0. GMS.extrusion-spheronization: process Variables and characterization Various researchers have used different types of equipment (friabilators or tumblers) for different times and with different speeds.or glycerol-containing pellets with coating.49. Lindner and Kleinebudde did not find any correlation between porosity and friability44 but Perez and Rabiskova did.7 P / (πd2/4) where St is the granule strength. and phase angle of such pellets. and d is the diameter of the granule. Bashaiwoldu et al.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. Umprayn et al.13 the friability values were less than 0. Both glass balls22.145: St = 0.43 by University of Hong Kong Libraries . deformability. During spheronization. and shear strength of the coated (aqueous dispersion of ethyl cellulose) and uncoated pellets were determined by conventional techniques.01% with an unacceptable reproducibility. http://dl. elastic modulus. did not. Kojima and Nakagami used a particle hardness tester and calculated the granule strength by the equation that was first given by Hiramatsu110. and rotation speed of the equipment also varies between researchers. including a diametral compression test of individual pellets and compaction of a bed of pellets.44 When they used the method reported by Zhang et al. different friability values were obtained by using different methods.28 The tensile strength. storage modulus. however.com Downloaded 2010-12-13 from IP 147.31. their size and shape. http://dl.e. The maximum crushing strength (σm) is calculated from the maximum applied load and the cross-sectional area of a pellet as described in the following equation: σm = 0. so the stress is always proportional to the measured force. however. and aspect ratio of pellets composed of Eudragit RS and Eudragit RL (1:0.147 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. the imposed strain is constant). sphericity. The low level of trapped water makes a significant contribution to the strength of the pellet by forming liquid bridges. Increasing the percentage of drug up to 60% decreased MDT but beyond that increased MDT.43 by University of Hong Kong Libraries . one step of stress is applied and the change in strain is measured for a certain period of time..91 Increasing the percentage of drug also decreased the elastic modulus of the pellets.91 evaluated MDT.begellhouse. suggested that the resistance of individual pellets to crushing is related to the cohesive and adhesive properties of the excipients. Eudragit RL PO compared with Eudragit RS PO resulted in pellets with high crushing strength. Dyer et al. 0:1) and % PVP (1.sinha et al. crushing strength. the Eudragit type did not have a significant effect on elastic modulus. 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. thereby trapping some water in the pellets. elastic modulus. This statement is valid only when all of the pellets are very similar in shape and size. Cespi et al.146 Abbaspour et al.8. 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. Increasing the percentage of PVP slightly decreased MDT and elastic modulus but had negligible effect on crushing strength. as well as other properties that are specific to the manufacturing process. a porous pellet with reduced mechanical strength may be produced. 5). 314 Begell House Digital Library. provides a barrier to further moisture transfer.4Pm / πr2 where Pm is the maximum load at failure (N) and r is the radius of the spherical pellet (m).146 The crushing strength of the pellets can be determined by using a universal compression tester. 1:1.3 On drying. surface characteristics. 3. in the second test. In the first test. a constant strain is applied and the stress is measured for a certain period of time. whereas the stress relaxation tests provided information about their deformation ability (viscous flow) and residual elasticity (stress relaxation modulus).31. 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. pellet characteristics are fundamental. In fact.43 by University of Hong Kong Libraries .147 concluded that the granule crushing strength was extremely useful in predicting the fragmentation aptitude of the pellets.extrusion-spheronization: process Variables and characterization Crushing strength tests provided information of both the mechanical strength and the fragmentation aptitude. The relaxation time and the relaxation modulus were not proportional to the pellets composition but they were minimal at a particular lactose-cellulose ratio. The above con- 315 Begell House Digital Library. Loosely packed pellets have greater arch strength due to the formation of bridges and therefore may be considered more resistant to flow.148–154 and their influence on compression behavior and tablet properties60.62.8. as previously stated. Single pellet mechanical properties such as tensile strength (or crushing strength) and elastic modulus28.53.D. Deforming pellets are more suited than fragmenting pellets. The tapped density of pellets. In addition.begellhouse. resulting in larger Carr’s indices (described below). Cespi et al. Bulk density is dependent on particle packing. VII. The stress relaxation test performed on the different batches of pellets allowed a direct comparison of their deforming behavior. the quotient of the weight of the pellets and its final volume after tapping until the time when the volume does not decrease anymore. highly textured pellets will more readily form arches or bridges within the bed. Density Bulk density is indicative of the packing properties of particles and is greatly influenced by the diameter of the spherical granules.155–157 are important transient rheological parameters as factors for the prediction of the pellets’ ability to be compressed into tablets.com Downloaded 2010-12-13 from IP 147. 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. 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. http://dl. can be measured using an automated tapper. among these parameters. The interlocking of nonisometric or less spherical. It can be measured by the solvent displacement method at low pressures. • Any significant variation in the density of pellets will affect the batch size determinations in the coating equipment.5 gm/cm3) and another with high density (2. as determined by air pycnometry. siderations assume negligible electrostatic interaction between the pellets and handling in a consistent manner. Carr’s index indicates the percentage compressibility involved and lower values indicate better flow of the granules. The true volume is the difference in the granule volume and the pore volumes. If the density of the pellets varies significantly from batch to batch. one with low density (1. • During mixing of granules.8 gm/cm3).161 They used two types of pellets. therefore.sinha et al. In this case. Many researchers have assessed the influence of density on the gastric transit of pellets.begellhouse.43 by University of Hong Kong Libraries .24 Carr’s index (Ic) can be calculated as given below159. compressibility is a misnomer as no compression is involved. They studied the mean transit time taken by the pellets to transmit through the small intestine. The quotient of the tapped density to its bulk density is known as the Hausner ratio (HR)158: where ρt is the tapped density. A high Hausner ratio indicates increased cohesion between particles and.com Downloaded 2010-12-13 from IP 147. The true volume can be measured by a pycnometer.31. showed that density can influence gastric emptying and therefore has important implications for the formulation of controlled-release forms.160: Ic = (ρt – ρb) / ρb. and ρb is the bulk density. differences in densities may cause their segregation or inefficient mixing.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.161–168 Devereux et al. the potency of the finished capsule will also vary. Granule density indicates the extent of densification or compactness of substances. http://dl. poorer flow.8. the time taken for 50% of the pellets to 316 Begell House Digital Library. The granular volume includes the pore volumes of the particles. 43 by University of Hong Kong Libraries .59) dosage forms.1 Bogentoft et al.03 to 1. They found that the heavier pellets were retained in the stomach for a longer time than the lighter pellets.165 Kaniwa et al. administered single units ranging in density from 1.70 A water content of 35–40% (w/w) produced pellets with the highest bulk and tapped densities.8 g/ cm3. Umprayn et al. There was. More binder resulted in a product with fewer pores.0 to 1.94 and 1.166 Gruber et al. examined the gastric emptying of units of a much wider density range (0. Davis et al. Sangekar et al. Bechgaard and Hegermann reported that an increase in density from 1.168 They reported that density did not influence gastric retention.2 and 1.96 gm/cm3. found no difference between pellets of densities of 0.6 g/cm3 significantly delayed average transit time of pellets in human subjects with ileostomies. The conclusions drawn by different researchers on the influence of density on GI transit of pellets differ.164 Bechgaard et al. and the time taken for 50% of the pellets to arrive at the caecum.96 gm/cm3 were not significantly different.9 gm/cm3) in fasted dogs.begellhouse. increasing water content produced bigger pellets that packed less well and showed lower densities. no statistical difference in the small intestine transit time and the time for 50% of the pellets to arrive at the caecum. found that the mean gastric emptying rates of pellets of densities 0.56 317 Begell House Digital Library. Granule density and porosity are interrelated and are dependent on the water content and amount of binder. http://dl. Higher water content during the extrusion process will result in higher porosities and thus lower granule density.21. With low water content. also obtained decreased bulk and tapped densities with an increase in the amount of water. failed to confirm these differences in normal human subjects with pellets of densities 1. This effect was minimized at higher water contents.96) and nonfloating (specific gravity 1. whereas the presence of food did in both cases. however.31.8.92 gm/cm3 but did not observe any differences in gastric emptying rate.163 Kaus et al.44 Pellet densities were calculated for pellets of MCC with different concentrations of moisture.94 and 1.61 gm/cm3 and observed no differences in travel. Beyond this.5–2.com Downloaded 2010-12-13 from IP 147. administered units ranging in density from 1. the effect of the amount of binder was more pronounced.44 Evaporation of water from the pellets leads to the formation of pores.extrusion-spheronization: process Variables and characterization empty from the stomach.167 Similarly.162 They concluded that gastric emptying appeared to be independent of density. compared the gastric retention of floating (specific gravity 0.29 to 1. 171 MIP is based on intrusion of mercury into the pores of a solid sample and is quantified using the Washburn equation172: Pr = −2 γ cos θ where P is pressure (Psia). corroborating reports by other researchers. Microwave-drying of the same granules at 130°C led to a faster and uniform evaporation of water. water required for granulation. and consequently. dissolution. Porosity Porosity is a measure of void spaces in a material and can be calculated using a number of techniques. gas adsorption. Almost all of the water content was evaporated in the first few minutes of the process. and porosimetry. VII. A processing period of 2–10 min increased the pores and the total pore surface area and decreased the pore diam- 318 Begell House Digital Library. the shrinking of the pellets reached the smallest value.178.173–177 Mehta et al.111. can be measured by gas adsorption and MIP.31. such as density determination. http://dl.58 At higher drying temperatures the granules shrank. found a significant effect of various factors such as drug loading. 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. In this case. Total porosity of the pellets increased with the addition of water for granulation values from 60–70% w/w.begellhouse.179 Porosity parameters were also found to change with duration of spheronization.111 Pellets with low drug loading showed increased pore surface area with small mean pore diameters and an increased number of total pores. the matrix structure remained intact in the majority. which resulted in higher granule densities. whereas MIP is capable of measuring larger pores and interparticle spaces. γ is the surface tension of mercury (dynes cm-1).sinha et al. which resulted in the lowest granule densities. water displacement. The gas adsorption method is limited to pore diameters smaller than 2000 Å. and θ is the contact angle of mercury.8.155.44.E. Perez and Rabiskova found different granule densities for granules obtained after differing drying temperatures and drying methods. adsorption.170 Pore diameter and volume.43 by University of Hong Kong Libraries .169 Determination of pore structure can provide important information on disintegration. MIP has been extensively used in porosity determinations of granules. and diffusion of drugs. r is the radius of the pore (µm). and spheronization time on the porosity of granules.com Downloaded 2010-12-13 from IP 147. different results were obtained. residual surface energy. the dissolution rate of the pellets is also a function of spheronization time.22 Avicels of larger particle size produced pellets with larger intraparticular porosities.extrusion-spheronization: process Variables and characterization eter.181 Boutell et al. none of the porosity parameters was affected. VII.com Downloaded 2010-12-13 from IP 147.182 Use of high concentrations of polysorbate 80 imparted a degree of tackiness to granules. Flow Properties Many methods are available to measure the flow properties of pellets. producing a larger angle of repose and reduced flow velocity. Pellets containing barium sulfate were more porous. Pluronic solutions yielded pellets that were less porous than those produced using water. There are many fundamental properties of solid particles that influence their flow properties.15 Pellets prepared with glycerol also showed the same effect. Some of the common methods are angle of repose. Both the drying temperature and drying method influenced the porosity of granules. and subsequently their flow 319 Begell House Digital Library.43 by University of Hong Kong Libraries . particle size distribution. and flow-rate measurements.57. up to 20 min.8. shear strength determinations. the pellets became larger. This was attributed to a transition in the structure and particle bonding of the pellets. such as particle size. As expected.F. resulting in an increased porosity. whereas the use of sodium lauryl sulfate did not influence the porosity parameters.57–59 Increasing the drying temperature increased shrinkage of the granules. Microwave-drying excluded shrinking due to immediate water evaporation.182 With the increase in water content of the granulations. When the pellets were dried by different methods. when the percentage porosity again started to decrease.181 A remarkable effect occurred when the granulation liquid contained more than 40% 2-propanol. particle shape.begellhouse.180. thereby reducing the porosity. and surface area. studied the effect of additives on pellet porosities.31. http://dl. surface texture or roughness. The type of Avicels used in spheronization affected the pellet porosities. which provided pellets of nearly the same dimensions as wet pellets. beyond this time. Increasing the fraction of 2-propanol resulted in higher values for the porosity of the granules.141 The angle of repose is commonly used as a parameter for evaluating interparticulate forces of powders or granules. the pellet flow rate decreased. as did freeze-drying.70 With further increases in the water content. 43 by University of Hong Kong Libraries . Another torque parameter. http://dl. in turn. Soh and colleagues have demonstrated the usefulness of torque rheometry as a simple. 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.G.31. torque rheological properties of MCC-lactose binary mixtures (3:7) can also be determined and their respective torquemax(blend) and CEM(blend) values derived.65 Gomez-Carracedo et al. demonstrated the feasibility of using torquemax(blend). The surface texture and the inner structure of the pellets strongly depend on drug proportion. and drying conditions. adhesion to various substrates. and speed of the mixer blades. Image analysis of SEM micrographs is used to extract quantitative information of fractal geometry and surface texture. reliable. mixing time.8. 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. reflect the performance of different MCC grades in extrusion-spheronization. flowability. CEM(MCC). which would.com Downloaded 2010-12-13 from IP 147. MTR monitors simultaneously the changes occurring in a powder mass with different binder concentration. cumulative energy of mixing (CEM). additives and spheronization.sinha et al. composition and volume of the wetting liquid.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.183 This study explored the feasibility of predicting the quality of MCC pellets prepared by extrusion-spheronization using torque rheological characterization. Pellets produced using a very high amount of water (45% w/w) were too large for flow measurements. Soh et al. through the orifice became poorer. wettability. 320 Begell House Digital Library. and competent preformulation tool to predict the quality of MCC pellets prepared by extrusion-spheronization. Additionally. and critically determine the relevant properties such as friability. and CEM(blend) values of MCC grades to predict the quality of their resultant pellets. Surface Texture Morphological examination of the surface and internal structure of the dried pellets can be carried out using a scanning electron microscope (SEM). and drug delivery behavior.begellhouse. VII. Mixer torque rheometry (MTR) can be used to characterize the rheological properties or cohesiveness of moistened powder masses during mixing. A decrease in extrusion force was observed with increasing water content. consequently.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. plasticity. screen hole diameter. an attempt has been made to outline the general concepts of pellet preparation by extrusion-spheronization. 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. size distribution. and temperature have a high impact on the sphericity and size of the pellets. and/or orientation of the pixels. 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. density.31. extruder type. It is concluded that extrusion operational variables such as screen pressure (extrusion force). surface texture. silica gel. size. 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.13 VIII. The type of extruder influences the extrude quality and. and pore size distribution. amount. screw speed. mean pore size. This approach has proven to be useful for the evaluation of the roughness of the pore surface of different materials such as coal. friability. 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. The type. http://dl. and time are the major operational variables that affect the quality (pellet diam- 321 Begell House Digital Library. To accomplish this. However. The relationship between these variables and water content has also been discussed. porosity.43 by University of Hong Kong Libraries .extrusion-spheronization: process Variables and characterization Image texture provides information about the structural order of the surfaces as a function of the intensity. In this review. speed. drug release. and flow properties. and drug affect both the extrusion and the spheronization processes. and quantity of the granulating liquid. 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