About Authors:
Kapil Sharma*, Priyanka Sharma**
*M.Pharm, Yaresun Pharmaceutical Pvt Ltd, India
**M.Sc, Yaresun Pharmaceutical Pvt Ltd,
Rajasthan, India.

Pellets are spheres of varying diameter depending on the application and the wish of the producer. Applications are found not only in the pharmaceutical industry but also in the agribusiness (e.g., fertilizer, fish food) and in the polymer industry.
In the pharmaceutical industry, Pellets can be defined as small, free-flowing, spherical particulates manufactured by the agglomeration of fine powders or granules of drug substances and excipients using appropriate processing equipment. The term also has been used to describe small rods with aspect ratios of close to unity.

Traditionally, the word pellet has been used to describe a variety of systematically produced geometrically defined agglomerates obtained from diverse starting materials utilizing different processing conditions. Pellets for pharmaceutical purposes are usually produced in the size range of 0.5 to 1.5 mm. The final oral multiple-unit dosage form can be either a hard gelatin capsule filled with pellets or a tablet composed of carefully compressed pellets. Pellets are prepared using different technologies such as layering of the drug solution, suspension or powder on the inactive cores, extrusion/spheronization, and agglomeration in rotogranulators or rotoprocessors, compression, spray drying, or spray congealing.


1.1Advantages and Applications
i.    Flexibility in dosage form design and development
ii.    It permits the combination of  different release rates of the same drug in a single dosage form
iii.    Controlled release technology
iv.    Disperse freely in the GI & invariably maximize drug absorption
v.    Reduce peak plasma fluctuation
vi.    Minimize potential side effects without lowering bioavailability
vii.    Avoiding high local concentration
viii.    Less susceptible to dose dumping
ix.    Reduce gastric emptying rates so minimize inter and intra subject variability of plasma profile
x.    Pellets have a low surface area to volume ratio and provide an ideal shape for the application of film coatings
xi.    Reproducible fill weights in capsules
xii.    Can be used to mix incompatible drugs



Delivery Technology




Delayed-release pellet system

Dr. Reddy’s

Cardizem CD 360mg


Once-daily pellets system




Slow-release pellets system

Merck Lipha


Isosorbide dinitrate

Slow-release pellets system

Merck Generika



Slow-release pellets system



Isosorbide mononitrate

Slow-release pellets system


Table 1. Some examples of marketed pellets formulations.

2. Pellet Formation and Kinetics
Fine powders can readily be formed into agglomerates by the introduction of a liquid phase followed by suitable agitation or tumbling. The liquid and solid phases are brought into close contact; this allows binding forces to develop and bring about agglomeration. Growth of the particles occurs either by collisions and successful adherence of primary feed particles onto which particles collide and attachés themselves. This result in pellet growth formation.

When two particles come into close contact, the cohesive forces that hold the particles together are:

i.        Intermolecular attractive forces: these are very short range attractions, active up to a maximum of 103 ?. on the whole, van der Walls dispersive forces makes the most significant contribution.

ii.      Electrostatic attractive forces: these are almost always present in particulate systems. They are produced primarily by inter-particle friction. Although these forces are generally less than those experienced in other binding mechanisms, the net effect is to hold or orient particles in a contact region for sufficiently long for other, more dominant mechanism to operate.

iii.    Liquid bridge modes: these are three physical situations in which the amount of liquid present produces cohesive forces between particles. The contributing mechanisms are adsorbed liquid layers, mobile liquid bridges, and viscous or adhesive binders. Once sufficient liquid is present to produce liquid bridges in an assembly of particles, the cohesive strength of the material increased.

Beyond this nucleation phenomenon, the change in size can occur by a number of mechanisms. The prevailing mechanisms depend on factors such as the solid properties, liquid properties, and mode of operation. After nucleation has occurred, the predominating growth mechanisms are; (i) coalescence, and (ii) layering of either feed particles or fines from the breakdown of established agglomerates.

Binders can contribute significantly to agglomerate strength. Binders are additives that impart cohesive properties to the powdered materials through particle-particle bonding. Apart from imparting strength to pellets, binders also improves the flow properties by appropriate formulation of the pellets with the desired pellet size and hardness.

2.1 Techniques of Pelletization
Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units, referred to as pellets. Generally of size range 0.5-1.5 mm.

2.1 Powder Layering
Powder layering involves the deposition of successive layers of dry powder of drug or excipients or both on preformed nuclei or cores with the help of a binding liquid. Because powder layering involves the simultaneous application of the binding liquid and dry powder, it generally requires specialized equipment. The primary equipment-related requirement in a powder-layering process is that the product container should have solid walls with no perforations to avoid powder loss beneath the product chamber before the powder is picked up by the wet mass of pellets that is being layered on.

Figure 2.1 Powder layering process.

The first equipment used to manufacture pellets on a commercial scale was the conventional coating pan, a machine that has been used by pharmaceutical firms, primarily for sugar coating, for a long time. The conventional coating pan became the first pharmaceutical equipment used not only to manufacture nonpareils but also to develop sustained-release products of a number of prescription drugs using non-pareils as starter seeds. Conventional coating pans, however, have had significant limitations as pelletization equipment. The degree of mixing is very poor, and the drying process is not efficient. Mixing is a function of the pan shape, the tilt angle, the baffle arrangement, and the rotational speed of the pan itself. These parameters must be optimized to provide uniform drying and sufficient particle movement to eliminate the potential formation of dead spots during the operation and to maximize yield.
During powder layering, a binding solution and a finely milled powder are added simultaneously to a bed of starter seeds at a controlled rate. In the initial stages, the drug particles are bound to the starter seeds and subsequently to the forming pellets with the help of liquid bridges originated from the sprayed liquid. These liquid bridges are eventually replaced by solid bridges derived either from a binder in the application medium or from any material, including the drug substance, that is soluble in the liquid. Successive layering of the drug and binder solution continues until the desired pellet size is reached. Throughout the process, it is extremely important to deliver the powder accurately at a predetermined rate and in a manner that maintains equilibrium between the binder liquid application rate and the powder delivery rate. If the powder delivery rate is not maintained at predetermined equilibrium levels, over-wetting or dust generation may occur, and neither the quality nor the yield of the product can be maximized.

Pieces of equipment that overcame the limitations of coating pans and revolutionized powder-layering processing as a pelletization technique are tangential spray or centrifugal fluid-bed granulators. Although tangential spray equipment was originally developed to perform granulation processes, its application was later expanded to cover other unit operations including the manufacture and coating of pellets.

Micronizing or finely milling the drug before layering improves the efficiency of the layering process significantly and provides morphologically smooth pellets that are suitable for film coating. However, in the majority of cases, Micronisation tends to impact flow and thus the delivery rate, a critical process parameter. Therefore, it is likely that during processing, powders may adhere to the sides of the hopper or the feed screw and may even form rat holes within the hopper. To improve the flow properties of the drug substance, glidants are incorporated into the powder before processing. Chemically, glidants could be hydrophobic or hydrophilic and are chosen based on the type of formulation selected.

Finally, the rheological properties of the binding liquid, the liquid application rate, and drying air temperature should be optimized to produce the desired product temperature. In addition, the powder should be delivered at a rate that maintains a balance between the surface wetness of the cores and powder adhesion.

 2.2  Solution/Suspension Layering
During processing, all the components of the formulation are first dissolved or suspended in an appropriate quantity of application medium to provide a formulation with the desired viscosity and is then sprayed onto the product bed. The sprayed droplets immediately impinge on the starter seeds and spread evenly on the surface, provided the drying conditions and fluid dynamics are favorable. This is followed by a drying phase that renders dissolved materials to precipitate and form solid bridges that would hold the formulation components together as successive layers on the starter seeds. The process continues until the desired quantity of drug substance and thus the target potency of the pellets are achieved.

Figure 2.2  Solution/suspension layering.

2.3  Extrusion-Spheronization
Extrusion–spheronization is a multistep process involving a number of unit operations and equipment. However, the most critical pieces of processing equipment that, in effect, dictate the outcome of the overall process are the extruders and the spheronizers.
A variety of extruders, which differ in design features and operational principles, are currently in the market and can be classified as screw-fed extruders, gravity-fed extruders, and ram extruders. Screw-fed extruders have screws that rotate along the horizontal axis and hence transport the material horizontally; they may be axial or radial screw extruders (Fig.3). Axial extruders, which have a die plate that is positioned axially, consist of a feeding zone, a compression zone, and an extrusion zone. The product temperature is controlled during extrusion by jacketed barrels. In radial extruders, the transport zone is short, and the material is extruded radially through screens mounted around the horizontal axis of the screws.

Figure 2.3.A Schematic representation of screw-fed extruders: (A) axial extruder and (B) radial extruder.

Gravity-fed extruders include the rotary cylinder and rotary gear extruders, which differ primarily in the design of the two counter-rotating cylinders (Fig.4). In the rotary-cylinder extruder, one of the two counter-rotating cylinders is hollow and perforated, whereas the other cylinder is solid and acts as a pressure roller. In the so-called rotary-gear extruder, there are two hollow counter-rotating gear cylinders with counter-bored holes.

Figure  2.3.B Schematic representation of gravity-fed extruders: (A) rotary-cylinder extruder and (B) rotary-gear extruder.

Figure  2.3.C  Mechanism of spheronization. transition from cylindrical particles into cylindrical particles with rounded edges, dumbbells, ellipsoids, and spheres.

2.4 Spray Drying and Spray Congealing
Spray drying and spray congealing, known as globulation processes, involve atomization of hot melts, solutions, or suspensions to generate spherical particles or pellets. The droplet size in both processes is kept small to maximize the rate of evaporation or congealing, and consequently the particle size of the pellets produced is usually very small.
During spray drying, drug entities in solution or suspension are sprayed, with or without excipients, into a hot air stream to generate dry and highly spherical particles. As the atomized droplets come in contact with hot air, evaporation of the application medium is initiated. This drying process continues through a series of stages whereby the viscosity of the droplets constantly increases until finally almost the entire application medium is driven off and solid particles are formed. Generally, spray-dried pellets tend to be porous.
During spray congealing, a drug substance is allowed to melt, disperse, or dissolve in hot melts of waxes, fatty acids, etc., and sprayed into an air chamber, where the temperature is below the melting temperatures of the formulation components, to provide spherical congealed pellets under appropriate processing conditions. A critical requirement in a spray congealing process is that the formulation components have well-defined, sharp melting points or narrow melting zones. Because the process does not involve evaporation of solvents, the pellets produced are dense and non-porous.

2.5  Cryopelletization
Cryopelletization is a process whereby droplets of a liquid formulation are converted into solid spherical particles or pellets by using liquid nitrogen as the fixing medium. The procedure permits instantaneous and uniform freezing of the processed material owing to the rapid heat transfer that occurs between the droplets and liquid nitrogen. The pellets are dried in conventional freeze dryers. The small size of the droplets and thus the large surface area facilitate the drying process.

 2.6 Melt Spheronization
Melt spheronization is a process whereby a drug substance and excipients are converted into a molten or semi-molten state and subsequently shaped using appropriate equipment to provide solid spheres or pellets. The process requires several pieces of equipment such as blenders, extruders, cutters (known as pelletizers in the plastics industry), and spheronizers. The drug substance is first blended with the appropriate pharmaceutical excipients, such as polymers and waxes, and extruded at a predetermined temperature. The extrusion temperature must be high enough to melt at least one or more of the formulation components. The extrudate is cut into uniform cylindrical segments with a cutter. The segments are spheronized in a jacketed spheronizer to generate uniformly sized pellets. Depending on the characteristics of the formulation ingredients, pellets that exhibit immediate- or sustained-release characteristics can be manufactured in a single step. The pellets produced are unique in that they are mono-size, a property unmatched by any other pelletization technique. However, the process is still in the development stage, and additional work is needed before the process becomes a viable pelletization technique.

2.7  Spherical Agglomeration
Spherical agglomeration, or balling, is a pelletization process in which powders, on addition of an appropriate quantity of liquid or when subjected to high temperatures, are converted to spherical particles by a continuous rolling or tumbling action. Recent technologies used for spherical agglomeration are rotary fluid-bed granulators and high-shear mixers. Spherical agglomeration can be divided into two categories— liquid-induced and melt-induced agglomerations.


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