Pellets are methodically prepared agglomerates of varied starting materials obtained from different processing techniques. They are spherical in shape and range from 0.5 mm to 1.5 mm in diameter. They are used as oral dosage forms facilitating improved flow properties and various other formulation characteristics. Pellets can be consumed directly or may be formulated in tablets or capsules. Pellets are not a uniform blend of active ingredient and other excipients but consist of a drug core surrounded by layers of other excipients and finally covered by a polymer coating. This makes pellets more desirable than granules since the quantity of drug incorporated is much larger and the particle morphology is desirable.

Regardless of the pelletization procedure involved, all pellets must show certain characteristics as listed below:
•    Pellet surface should be smooth and shape as spherical as possible.
•    Size of the pellet should be between 600 to 1000 microns.
•    It should incorporate maximum possible active ingredient in order to maintain the shape of the pellet.
Pellets have been introduced in the recent past due to their remarkable advantages and desirable characteristics. They can be used as multiple unit dosage forms (MUDFs) or can be worked into tablets or capsules. Their shape and size facilitates excellent flow properties and good packing capability thus making them suitable for tableting. Being polymer coated pellets can be used to formulate single dosage form for chemically compatible and incompatible drugs, release at various sites in the gastrointestinal tract and different release rates. Thus making them more desirable compared to conventional unit dosage forms.

Techniques and equipments
Dry powder layering: This technique involves coating of a preformed core or nucleus with a mixture of the drug and excipients using a binder solution. The nuclei are placed on a starter bed and the milled material along with the binder solution is introduced simultaneously at a predetermined rate. The particles coat the core and form a powder layer which with the help of the binder solution forms liquid bridges. These are then converted to solid bridges on drying. Subsequent layering of drug and binder solution on the core is continued to attain the desired pellet size. The conventional coating pan has been used for this technique. However, it exhibits a considerable amount of limitations. The mixing capacity is poor and drying is not efficient. It is essential that the powder flow is uniform at predetermined rate such that binder solution and the particle flow is in equilibrium otherwise there may be over wetting or formation of fines due to improper binding. Hence the nuclei kept in constant motion with the milled powder mixture with the binder liquid sprayed onto the moving particles. This improves surface wetting and adherence of fines to the pellets yielding a smooth regular surface finish. This is achieved by the use of equipment like tangential spray granulator or centrifugal bed granulator.

Solution/suspension layering: The basic concept is similar to the dry layering as mentioned above. Instead of milled powders and binder solution, a solution or suspension of the drug in the binder liquid is made and sprayed in the inert nuclei. These nuclei may be inert particles or cores of the same drug material. The droplets attach to the surface of the nuclei and form an even coat. This is then followed by a drying stage which allows the dissolved drug to solidify and form crystalline solid bridges on the core, between successive layers and final polymer coat. When using suspension since the drug is not solubilised, it is necessary to maintain small particle size. Drugs with large particle size of suspension require higher quantity of liquid and give irregular finish to the final product. Micronized particles are used to avoid this problem as they give a smooth finish to the product which is highly essential for uniform polymer coating on the pellet. Conventional coating press and fluidized bed centrifugal granulator have been successfully used to form pellets.

Extrusion-Spheronization: This technique was developed in the 1960s for pelletization. In case of formulation of controlled and modified release dosage forms, the pellets must possess a smooth surface and narrow particle size range. This facilitates optimum flow property and ensures uniform coating. The aim is to have uniform pellets or spheroids with a high drug loading capacity and better particle morphology. This is a multiple step process and is carried out as follows:
•    Dry mixing: This involves mixing of all the dry ingredients of a desired particle size so as to form homogenous powder dispersion. This is done using twin shell mixer, high shear mixer, tumbler mixer or planetary mixer.
•    Wet massing: The dry mix is wetted sufficiently to a plastic mass using planetary mixer, sigma blade mixer, high shear mixer or Horbat mixer.
•    Extrusion: This is the major stage essential for proper spheronization. In this, the suitably moistened mass is passed through the extruder screen or die plate which has holes of calibrated diameter. It results in formation of long cylindrical masses of a definite diameter. The size of these ultimately determines the final pellet size. These masses should be brittle enough to break into smaller cylinders due to their own weight. They should be plastic enough to deform but not excessively plastic that it may lead to sticking and further complications in the process. Feed rate, powder consumption, die temperature and compression chamber pressure should be monitored so as to obtain uniform and standard size of pellets in subsequent cycles. The equipment used includes screw feed extruders, gravity feed extruders or piston feed extruders.
•    Spheronization: This is the stage in which small cylinders are formed into spheres using spheronizer or marumerizer. The three stages of the process involve breaking of extrudates, agglomeration of broken segments and smoothing of particles. The breaking of extrudates takes place due to interaction with plates, walls or other extrudates. The broken masses are then spheronized by rolling the particles along their axis in various planes. These formed spheroids have sufficient plasticity to undergo remodelling but remains cohesive enough to maintain the integrity of the spheres.
•    Drying: The spheroids are then dried to achieve desired moisture content. This can be done at room temperature or at elevated temperatures, depending on the boiling point of the binder added, in tray dryers or fluidized bed dryers.
•    Screening: The final stage involves screening of all the pellets so as to achieve a narrow size distribution in the batch.
Cryopelletization: In this technique, liquid nitrogen is used to convert droplets of liquid formulation into solid pellets at extremely low temperatures of -1600°C. The rapid heat transfer between the droplets and the nitrogen facilitates uniform freezing of the processing material. It is used for forming high drug loaded pellets. The amount of liquid nitrogen used depends on the temperature and solid content of the solution or suspension. The equipment used consists of a container equipped with perforated plates, reservoir conveyor belt with transport baffles and storage container. The liquid is allowed to fall through the perforated plates into the nitrogen bath where they freeze and then are carried away to the storage before drying.

Melt or freeze pelletization: This is a novel pelletization technique which has great advantages in terms of process cost as well as quality of pellets. It can be used to form pellets of narrow size distribution and involves very less process variables thus making it efficient and simple. The processing material is introduced in the form of droplets of a melt of the solid product into a column of inert liquid.  The melts flow either downward or upward in the liquid column depending on the density of the material and come out as spherical solid pellets. The melts as drug carriers should be such that they are solid at room temperature and have a melting point below 100°C so as to minimize degradation of labile drugs. For hydrophilic carriers, liquid column of hydrophobic material is used and vice versa. For production of sustained release pellets including both hydrophilic and hydrophobic components, a liquid which is immiscible with both carriers is chosen as cooling liquid in the column. Various kinds of freeze pelletizers are used depending on the type of pellets to be generated.

Spherical agglomeration: It is also known as balling. The process involves powder pelletization with addition of suitable pelletizing liquid or processing at high temperatures which facilitates melting of excipients providing appropriate binding. The powder is converted to pellets by action of rolling or tumbling. This process is of two types:
•    Liquid induced agglomeration: The powders are introduced on a bed and liquid is added before or during agitation. The liquid helps bind the particles via liquid bridges which are then converted to solid bridges by solidification of binder liquid. They form agglomerates which collide with other particles for form larger coalescence. The nuclei enlarge to a particular size at which point coalescence stops and smaller particles form layers on larger ones to give pellets.
•    Melt induced agglomeration: In this process melts are used instead of binder liquid. Hence the particles agglomerate by congealing rather than formation of liquid bridges. The formed pellets do not posses optimum moisture and the particle size range is wide.
Globulation
It consists of two related processes:  Spray drying and spray congealing.
•    Spray drying: The drug is dispersed or dissolved in a suitable medium. The liquid is then sprayed through an atomizer to form very small droplets. The spray passes into a chamber maintained at a high temperature. The droplets have a large surface area due to small size and hence undergo quick evaporation allowing the solvent to escape and forming small uniform sized spherical particles. The process is commonly used for improving dissolution rates and increasing bioavailability of insoluble drugs. The process is continued in stages till viscosity of particles increases to an extent at which all the solvent is driven off and solid particles remain. Pellets formed by this method tend to be porous.
•    Spray congealing: Unlike spray drying, spray congealing uses a melt of the drug substance mixed with hot melts of waxes or gums. These are sprayed into a chamber maintained at a low temperature. The droplets undergo cooling such that the drug material gets suspended in the coat of melted waxes. The resultant slurry is pumped into a spray dryer with circulating cold air. Coating materials normally used are low melting waxes. Both immediate release and controlled release pellets can be made using this technique depending on the physicochemical properties of the ingredients.
Excipients
Various excipients have been used for formulation of pellets for different active ingredients. The most commonly used extrusion spheronization excipient is microcrystalline cellulose (MCC). It can be used for pellets to be filled in hard gelatin capsules or compressed into tablets. Various derivatives of celluloses have been used including different grades of Avicel (usually Avicel PH 101), Avicel with 5% methyl cellulose or 6-8% sodium carboxy methyl cellulose (SCMC) and mixtures of MCC with hydroxyl propyl methyl cellulose (HPMC) . MCC and cellulose derivative mixtures are used for pellets of high drug loading capacity upto 80%. Mixtures of corn starch and wheat starch with addition of 20% dextrin give high quality pellets with good shape and size distribution. Starch and other polysaccharides like dextrins are also mixed with MCC as excipients. A very low soluble derivative of pectin called pectinic acid is also a well suited for pelletization. Although it is not as universal as MCC, pectinic acid can be used with lactose in different ratios as excipient for pelletization. It is highly effective in combination with lactose, with concentrations ranging from 20-80%. Pectinic acid gives almost spherical pellets with good mechanical strength and solubility. Alginate and chitosan are also used with MCC. Chitosan imparts better disintegration profile to the pellets. 20% carrageenan with lactose, mannitol, maize starch or dicalcium phosphate dihydrate can also be used.

Synthetic polymers like polyacrylates, acrylic resins, carbopol can be mixed with MCC in concentrations ranging from 10 - 55% and used. Polyvinyl pyrrolidone (PVP) is an excellent binder along with MCC.

For spray dried pellets, excipients used include mixtures of MCC with HPMC, hydroxyl propyl cellulose (HPC), SCMC and PVP with 20% lactose usually preferred, HPC and PVP being the most favoured polymers due to maximum yield of spherical pellets.

Processes like spray congealing and melt or freeze pelletization require excipients like hydrophilic and hydrophobic meltable binders. Hydrophilic binders include Gelucire, Poloxamer, Polyethylene Glycol (2000, 3000, 6000, 8000, 10000, 20000) and stearates. Hydrophobic binders include beeswax, carnauba wax, cetyl palmitate, glyceryl monostearate, glyceryl palmitostearate, glyceryl stearate, hydrogenated castor oil, microcrystalline wax, paraffin wax, stearic acid and stearic alcohol.

Advantages
Pelletization techniques have greatly advanced the delivery of oral medications due to their various advantages:
•    Improved appearance of product
•    Better flow properties and packing leading to uniform tablet and capsule fill size
•    High bulk density
•    Better strength, reduced abrasion and less friability
•    Improved safety and lesser toxicity of active ingredient
•    Reduced hygroscopicity
•    Resistance to precipitation or crystallization of drug in suspensions or solutions
•    High drug loading capacity without producing large particles
•    Reduced dosage frequency due to extended drug release
•    Less susceptible to dose dumping when formulated as modified release dosage forms, thus less risk of side effects
•    Reduced accumulation of drug in GIT hence preventing irritation to gastric mucosa
•    Freely disperse in gastric fluid providing large area of contact for better absorption and bioavailability and reduced peak plasma level fluctuations
•    Unpalatable drugs can be masked by pelletization
•    They can be used for separation of incompatible drugs or excipients and delivered as single dose after encapsulation
•    Mouth disintegration dosage forms can be formulated with good palatability and mouthfeel effect for paediatrics and geriatrics. These orodispersible medications can be administered without water, especially while travelling.
•    Multiple drugs formulated as single dosages thus lower the daily medication cost for patients
Applications
•    Pellets can be used to formulate various dosages as per patient convenience and for improved pharmacokinetic and pharmacodynamic profile.
    Tablets: Pellets may be compressed to form tablets which show different release parameters as compared to normal disintegrating tablets.
    Capsules: Pellets may be encapsulated in capsules to produce unit dosage forms.
    Multiple Unit Pellet System (MUPS): Pellets can be introduced as MUPS for oral absorption.
•    Taste masking: In order to mask undesirable taste of many drugs, various measures have been employed including addition of sweeteners and flavourants, encapsulation, water insoluble polymer coating, complexing with cyclodextrins, chemical modifications to prodrugs, etc. Micropellets not only effectively mask the taste of the drug but also maintain high bioavailability due to large surface area, especially of oral drugs. Many products known for repulsive taste like antibiotics and anti-inflammatory agents have been successfully masked by micropelletization yielding high patient compliance and hence better drug delivery.
•    Immediate release: In case of traditionally compacted tablets or capsules, disintegration time radically increases the time required for systemic action of the drug. Pellets having high drug load and high surface volume ratio are capable of providing better bioavailability with further reduction in time lag caused by tablet disintegration. Thus making them highly suitable for immediate release dosage forms.
•    Sustained release: Pellets have a more uniform absorption profile due to their ability to pass from the stomach to the intestine at a steady rate. Pellets can be formulated as sustained release or immediate release depending on the thickness of the final polymer coating applied to the pellet. As the thickness goes on increasing, rate of release is slower. Coloured polymer coats may be applied to identify thickness of polymer coat depending on intensity of colour. Round shape and smooth surface facilitates use of micropellets in powder injections. Due to high drug load capacity of pellets, low volume injectables can be formulated. Drugs like neuroleptics, peptides, hormones, vaccines, etc which require a slow and extended release of the active ingredient are prime candidates for parenteral depot technologies like micropellets. Biodegradable polymer coats of drug embedded in polymer matrix can be used for drug release over period of hours, days, months or even years thus preventing necessity of frequent injections which is inconvenient to patients.
•    Chemically incompatible products: Due to their ability to take up polymer coatings, chemically incompatible drugs can be formulated as pellets. Drugs may be chemically incompatible either with each other or other excipients. Pelletization facilitates delivery of multiple incompatible drugs in a single dosage form.
•    Varying dose without reformulation: As pellets are free flowing discrete entities, dosage can be altered merely by changing capsule size and quantity of pellets encapsulated instead of complete formulation revision.
•    (Dr Pradnya Palekar-Shanbhagr is associate professor in Pharmaceutics, Dept of Pharmaceutics, Vivekanand Education Society’s College of Pharmacy, Hashu Advani Memorial Complex, Chembur, Mumabi 400 074 and Ketaki Katdare is a B. Pharm student)