Multiunit Particulate Systems: A Current Drug-Delivery Technology

July 2, 2011
Pharmaceutical Technology

Volume 35, Issue 7

The current review describes the role and selection of excipients, pellet core, coating materials, and compression with various cushioning agents.

Oral drug-delivery systems are the most acceptable form of controlled-release system to patients. Scientists have shown growing interest in modified-release oral dosage forms in recent years. Current technologies, such as oral multiparticulate drug-delivery systems (MDDS), have gained immensely in importance, not only because of their ability to control drug release, but also for the modified drug-release profiles they facilitate.

These systems release the drug with constant or variable release rates, thus maintaining drug concentration within the therapeutic window for a prolonged period of time. The desired release profile facilitates controlled absorption through the target site in the body, ensures good therapeutic activity, and reduces side effects (1). MDDS comprises a large number of small discrete particles (i.e., active ingredient and excipients), each demonstrating desirable features. They are prepared by methods including extrusion–spheronization, pelletization, granulation, spray drying, and spray congealing.

Multiunit particulate systems

Multiunit particulate systems (MUPS) are a novel MDDS technique for controlled and modified drug delivery. MUPS offer various advantages over other systems, including reduced risk of local irritation and toxicity, predictable bioavailability, reduced likelihood of dose dumping, minimized fluctuations in plasma concentration of drug, and high dose-strength administration (1). Multiparticulate systems show more reproducible pharmacokinetic behavior and lower intra- and intersubject variability than conventional (i.e., monolithic) formulations (2). Tableting of pellets reduces the esophageal residence time, compared with capsules, and improves physicochemical stability, compared with suspensions (2, 3).

The applications for which MUPS formulations are developed include taste masking (i.e., orodispersible MUPS tablets), enteric-release (e.g., of acid-labile drugs), and modified- or controlled-release orodispersible drugs for geriatric or pediatric patients. The technology of preparing compacted MUPS ensures that the desired objectives (e.g., taste masking coupled with orodispersibility as well as modified-release characteristics) are effectively achieved.

A good example of a MUPS is AstraZeneca's Losec, an antiulcer drug, the second-highest-selling pharmaceutical product in Sweden in 2002 (3). The product consists of microencapsulated drug granules tableted with excipients (4). Other marketed MUPS formulations include Galanil PR (Galantamine HBr) for Alzheimer's disease, antiobesity drug Lipidown (Orilistat), and Esomezol (Esomeprazole Sr) for erosive reflux esophagitis, which are all manufactured by Hanmi Pharmaceutical.

Challenges in the formulation of multiunit particulate systems

Each discrete particle in a MUPS product incorporates its own release characteristics and further contributes to the product's therapeutic activity. Compressing these subunits without affecting their individual release profiles is a major challenge of MUPS technology because compacting subunits may lead to structural changes in the coating and consequently alter drug-release behavior (5).

Other challenges for manufacturing pellets in tablets (i.e., MUPS) are weight variation, poor hardness, and friability. To prevent subunits from being altered, formulators include a cushioning agent (i.e., an excipient with protective properties) in the tablet formulation.

The compression-induced changes in the structure of the subunits may depend on numerous formulation factors, such as the type and amount of coating, the properties and structure of the substrate pellets, and the incorporation of excipient particles. During MUPS formulation, scientists must consider process variables such as the nature of the polymer; the shape, porosity, and density of pellets; compression force and content of coated pellets in the tableting blend; the wall thickness of coating; and the nature of the excipients.

Figure 1: Pelletization process. (FIGURE IS COURTESY OF THE AUTHOR)

Pelletization and multiunit particulate systems

Pellets are manufactured by both wet and dry granulation techniques or by layering. Extrusion–spheronization is a wet-granulation technique that helps in the preparation of pellets or spherical agglomerates. The process involves a blending stage, in which active ingredients are blended with excipients and mixed with suitable binding solutions to form a heavy plastic mass. This mass is subjected to extrusion to form extrudates of equal length. After extrusion, the materials undergo a spheronizing stage that rounds extrudates by cutting them and rolling them into spheres (see Figure 1).

Figure 2: Pelletized tablet with drug embedded polymer matrix system. (FIGURE IS COURTESY OF THE AUTHOR)

Manufacturers create modified-release systems in two main ways. They either coat spherical, uncoated pellets or embed a drug in a polymer matrix system (6). The uncoated drug–polymer pellets prepared by extrusion–spheronization are subjected to compression into tablets (see Figure 2). In another technique, the polymer or release-controlling material is coated along with the drug onto the uncoated pellet to form a nonpareil seed (see Figure 3). These drug–polymer coated pellets are compressed into tablets to obtain MUPS.

Figure 3: Pelletized tablet with polymer coated pellets. (FIGURE IS COURTESY OF THE AUTHOR)

Compressibility and compactibility

The ability of a powder to decrease in volume under pressure is called compressibility, and the ability of the powdered material to be compressed into a tablet of specific strength is called compactability (7). According to one theory, the compaction sequence for elastic materials includes particle rearrangement, plastic deformation, and elastic deformation (8). In Van der Zwan and Siskens's theory of the compaction of pellets, the process of volume reduction involves the filling of interparticle voids, where the secondary particles undergo readjustment; the fragmentation and plastic deformation of secondary particles; the filling of intraparticular voids, where primary particles rearrange, making the mass more dense; and the fragmentation and plastic deformation of the primary particles (9).

In an entirely different theory of compaction and volume reduction, Johansson stated that the secondary particles rearrange to fill interparticle voids where the strength of the compressed powder is too low due to low bonding force. Next, the surfaces of the secondary particles are flattened with local deformation. Then, as secondary particles undergo bulk deformation, they simultaneously become densely packed, and bonding strength increases significantly. Finally, low inter- and intragranular porosity causes the compression process to stop with less volume reduction of the bed but with higher bonding within the particles (10).

The major challenge of a formulator is to retain pelletproperties after the compaction process. To aid formulators, this article will describe the factors involved in the compaction and consolidation of coated and uncoated pellets.

Compression of coated pellets

Preparing compacted MUPS (i.e., compressing coated pellets to achieve multiple objectives) is a challenging task. During compaction, the polymeric coating may not withstand the compression force, thus affecting the surface of polymer and the pellets, which could cause the drug to be released in an undesired manner.

Hence, thorough process optimization is needed for the compaction of coated pellets. The main variables involved are the compression force and the velocity of the punches. The hardness, thickness, and porosity of the tablets must be maintained. Other important factors concerning the preparation of multiunit tablets are the properties of the barrier coating and the inclusion of protective excipient particles in the tablet formulation, and these parameters have been investigated extensively.

Pellet core. Many formulators have successfully studied and investigated the compression behavior of pellets consisting of various excipients. The selection and study of the material used to manufacture pellets is important to achieve the desired release pattern (11). The comparison between soft and hard pellets revealed that the pellets with soft constituents had the greater chance that intergranular pore spaces would be filled because the primary particles can move within the agglomerate. Harder pellets tend to fail at the surface because of the pressure of compaction.

Nicklasson studied the behavior of microcrystalline cellulose (MCC), alone and in combination with polyethylene glycol and dicalcium phosphate pellets, during and after compression. He concluded that pellets are deformed after compression, depending on their capacity for, mode of, and resistance to deformation. Nicklasson also studied polyethylene glycol as a cushioning agent to analyze the compression behavior of pellets. For the study, he used MCC-based beads loaded with theophylline, which are hard, and softer beads prepared with glyceryl monostearate (12).

Wang attempted to study the compression of lactose and MCC in various concentrations of powder and pellets. MCC-based pellets lost their plasticity during granulation and hence showed poor compactability, compared with lactose-based pellets (13). Iloanusi and Schwartz studied the crucial role that plastic deformation plays in compression by adding wax to the MCC bead formulations. Pellets with wax as a cushioning agent had more compressibility than beads without wax as a compression modifier (14).

Salako confirmed the advantages of softening materials during compression. On application of initial compaction pressure, the soft beads ruptured. On further application of pressure, the beads deformed and formed a network. Because of the soft nature of the beads, the material readily underwent deformation and rearrangement. Harder pellets are compact, and upon the application of compaction pressure, they underwent reduction in volume by particle rearrangement, not because of bond formation, compared with soft pellets (15).

Salako conducted a similar study of pellets' deformability and tensile strength using MCC-based beads loaded with theophylline, which are hard. Soft pellets were prepared with glyceryl monostearate (15).

Pellets undergo structural modifications during compaction. They need elasticity and flexibility to withstand compaction pressure. The ideal pellets are strong, not brittle, and have a low elastic resilience. They should deform under load application and load recovery without fracture (16). Knowledge of the compression behavior of uncoated pellets can provide a basis for the manufacture of multiunit tablets from barrier-coated pellets without damaging their coating.

Size and shape. Pellets undergo deformation after compression. Hence, the size of the pellets affects their compaction properties and the drug release from compacted pellets. Large pellets tend to undergo deformation more readily than small ones. Small pellets are stronger than large ones; they withstand compression pressure with less deformation (17). The strength of the pellets affects the final strength of the compressed tablet and helps ensure the desired release rate.

Johansson proposed that the deformation of individual pellets could be correlated with their size. A higher degree of deformation was observed with large pellets than with small pellets. As the size of pellets increased, the number of force-transmission decreased, which increased the contact force on each pellet (18). Isometric-shaped pellets offered fewer contact points and more uniform drug release than anisometric-shaped particles.

In addition to size, the shape of pellets affects the compression behavior and tablet-forming ability of granular materials. Irregular shapes induce complex compression behavior in granules. They increase the attrition of the granules, thus resulting in increased deformation (19–20). Flament found that, after the application of similar quantities of coating on pellets, small pellets were more fragile than large pellets. The probable reason is that small pellets' increased surface area reduced the film-coating thickness (21). Furthermore, increases in particle size resulted in more damage to the coating, as indicated by larger differences between the release profiles of tablets and uncompressed pellets (20).

Beckert compacted coated pellets of two crushing strengths with different excipients and concluded that the harder pellets were better able to withstand compression forces because they deformed to a lesser degree and their film coatings were less susceptible to rupture (22). Ragnarsson found that the compaction of small pellets had less effect on drug release than the compaction of large pellets. He also concluded, however, that the effect of pellet size depended on the choice of coating material, as well as on the amount and properties of the pellets and the excipients forming the tablet (23).

Density and porosity. Pellet density and size play an important role in achieving content and weight uniformity. Because of their intragranular porosity, pellets tend to densify. By modifying their intragranular porosity, manufacturers can deform and densify pellets during compression (24–27). Pellets with a narrow size distribution and excipients of similar sizes, shapes, and densities can prevent segregation (28). The critical density for achieving prolonged gastric residence may be between 2.4 and 2.8 g/cm3 (29). The amount and choice of material used for binding or granulating the powders during pelletization, and the compaction pressure, have a direct effect on the porosity.

Unlubricated pellets also require higher pressures than lubricated pellets (5). A study by Bodmeier revealed that an increased proportion of water as granulating fluid in the mixture led to hard and less porous tablets with a slow drug-release pattern. Similarly, pellets prepared using 95% ethanol as a granulating fluid showed good compressibility in contrast with pellets prepared with water (5). Using 95% ethanol during granulation formed strong intergranular bonds with an increased porosity, which finally increased the deformation of the formed pellets during compaction into tablets.

Porosity also can affect drug release. Tuton showed that pellets of high porosity were densely packed and deformed, and that the drug release from these pellets was not affected. But upon compaction of pellets with low porosity, the pellets were compressed with slight densification and deformation, leading to increased drug release. Using highly porous pellets did not alter the drug release after compression, in comparison with pellets with low porosity (30).

Compression force. Compression force is a critical parameter that must be optimized during tableting of pellets. Several studies investigated the compression force required for compressing pellets and found that 15 KN was sufficient for tablets with smooth surfaces. Flament studied the compression of theophylline-loaded pellets with acrylic polymer. Upon the application of compression pressure, the pellets were compacted by deformation at 6 KN. Further investigation revealed that increasing the compaction force to 20 KN did not alter the dissolution rate significantly (21).

Protective particles. Protective particles, also known as cushioning agents, help prevent damage to the drug–polymer-loaded core pellets. Protective particles rearrange themselves between the pellets and reduce the void space to prevent direct contact of pellets after the application of compression pressure. Preferred excipients are agglomerates (e.g., pellets or granules) that lower the risk that pellets will separate by size or density during processing, thus leading to weight variation or dose nonuniformity. When used as cushioning agents, primary particles (e.g., powder) give rise to the above problems (16, 21, 31). The cushioning effect of an excipient depends on its particle size, volume, and compaction properties. The method by which the particles undergo volume reduction needs to be studied. Several studies proved MCC and polyethylene glycol to be good excipients for compaction because of their plastic deformation (22, 32–34). Studies also proved that lactose, which undergoes fragmentation upon compression, offers better protection than MCC (35).

However, studies of 14 excipients proved that excipients that show good plastic deformation during compression give the best protection to the coating material (36). Particle size is an important factor in preformulation, and some studies suggested that particles smaller than 20 μm prevent damage to the coating. Increased dissolution rate was observed with particles bigger than 20 μm (29, 37). Using wax as a cushioning agent during pellet compression also is of great help to the formulator because it prevents damage to the coating during compression (38).

Nature of polymer. Polymers play an important part in any controlled- or modified-release dosage form. The final release of the drug from the formulation depends on the polymer used. A polymer must have appropriate plastic and elastic properties to withstand the shear of compression and compaction. Various polymers currently used to modify the release of pellets are either cellulosic polymers (e.g., ethyl cellulose) or acrylic polymers (e.g., Divakar's Polex, Evonik's Eudragit, or BASF's Kollicoat). The most frequently used polymers to extend the release of water-insoluble drugs are ethyl cellulose and ammonio methacrylate copolymers (39). Film-forming polymers have satisfactory elastic properties that prevent the rupture of the coating polymer, and good plastic properties that prevent deformation during compression.

Studies revealed that not only does the coating material affect compression properties, but also the solution in which polymer is dispersed or dissolved. The process entails dispersing polymer in water as pseudolatex or dissol-ving the polymer in an organic solvent. Investigations were conducted on ethyl cellulose to study its sustained-release properties after coating and compression in tablets. Ethyl cellulose improved pellets' puncture strength and elongation by making them brittle. The mechanical properties of ethyl cellulose were less affected after it was plasticized with pseudolatexes (19). Beads composed of alternating layers of ethyl cellulose, drug, and cushioning agent are less brittle than those that include only drug and ethyl cellulose.

Chang and Rudnic found that the solvent-based coatings were affected less by compression than the aqueous-based coatings were. Solvent-based coatings improved flexibility and mechanical stability in comparison with aqueous-based coatings (40). The coated pellets ruptured on compression, which affects the film formed on the pellets' surface.

To minimize or overcome rupture during compression, Bodmeier suggested placing the compressed pellets in a hot-air oven above their glass-transition temperature (5). The brittle and elastic properties of MCC pellets were modified by applying a water-based ethyl cellulose coating to them. Thus, plastoelastic properties were introduced to the pellets after coating, which improved their deformation characteristics (31).

Bechard and Celik showed that aqueous dispersions of ethyl cellulose for compression into multiunit tablets can, however, lead to coating failure through the formation of cracks and flaws (31–32). Films formed with high elasticity and apparent Newtonian viscosity delivered the maximum protection to the pellet core and coating on compaction (16). Lehmann suggested that the coating should be elongated at least 75% at the break to prevent the coating from rupturing during compression (41).

Thickness of polymer coating. The amount of coating affects how much compaction can modify it. Applying a thick polymeric coating to the surface of pellets imparts good elasticity and crushing strength to them (22). Damage to the coated pellets thus can be minimized during compression by applying a thick, rather than thin, coating of polymer solution (21–22). Bodmeier observed increased elastic and plastic deformation upon application of thick coating (5). The thickness of applied coatings provides good resistance to frictional forces, thus showing a direct dependence of cracks and elasticity on the film. To prevent the coatings from rupturing during compaction, the coating should have good elasticity and flexibility and be able to undergo structural changes and adapt to the deformation process (16, 22, 40, 41).

Plasticizer. Plasticizers are added to polymeric dispersions, especially to water-dispersions, to lower their glass-transition temperature and expedite the coalescence of the distinct polymer particles in the dispersion. Thus, coalescence of polymer particles directly relies on the time and temperature of coating and postcoating processes. Onions proposed a two-stage theory for the process of coalescence of aqueous polymeric dispersions.

The first stage includes the evaporation of the aqueous layer and the formation of a dry, transparent, apparently continuous film on the surface of the coated material. The coalescence of distinct polymer particles is completed gradually in the second stage. The water in the interstitial spaces starts evaporating slowly, bringing the separate particles close to each other and finally fusing the particles to form a strong and continuous film on the surface of the coated material (42–43). Further studies revealed that the amount of plasticizer did not influence drug release from compacted reservoir pellets (44). The flexibility of the aqueous-based coatings was improved by adding plasticizers, but Aulton observed that plasticizers led to a reduction in tensile strength (45). Felton proposed that increasing plasticizer content would increase the tensile strength of film-coated beads. The increased degree of plasticization of the polymer made the film more elastic and allowed it to withstand the deformation process during compression (46).


With its promising controlled-release mechanism for oral delivery, MUPS will be a focus of future research and development. The selection of excipients plays a key role in the success of MUPS. A thorough understanding of the factors that affect the performance of MUPS helps the formulator tailor the drug-release profiles. MUPS may soon become one of the most popular oral controlled-release systems.

Mitesh D. Phale* is a scientist and Abhijit V. Gothoskar is a global technical manager, both at Divakar Chemicals, 203–204, Sant Bhavan, Sharma Industrial Estate, Walbhat Rd., Goregaon–East, Mumbai 400 063, Maharashtra, India,

*To whom all correspondence should be addressed.


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