INTRODUCTION:

Controlled drug delivery systems (CDDS) are gaining popularity over the conventional dosage forms. Amidst the broad classification of CDDS, the subcategorization of multiple unit dosage form poses several advantages over the single unit CDDS¹. A pellet can be defined as a solid doage form, agglomerated from various starting materials, which functions as a multiparticulate controlled drug delivery system. Since the 20^thcentury, technique of pelletization was known. Pharmaceutical industries showed an interest in pelletization in the early 1950s, due to increased requirement for sustained release preparations². Pelletization is a process of size enlargement wherein the final product obtained has a spherical appreance, with dimesnions of 0.5-2 mm and has a reduced intra-agglomerate porosity³. Pellets are mostly intended for the use of oral preparations. Pellets offer therapeutic advantages such as improved absorption as larger surface area is exposed for absorption, reduced occurrence of dose dumping and hence lesser gastric irritation^2,3.

Owing to small size of pellet, they traverse across the pyloric sphincter from where they reach the small intestine and reach the ileocaecal sphincter irrespective of the gastric content^4,5. This characteristic is exceptionally important for the predictable delivery of Active Pharmaceutical Ingredients (APIs), while it may result in lower fluctuations of their plasma levels⁶.

They also provide certain advantages from a technical aspect such as enhanced flow properties owing to uniform size and spherical shape of particles, improved physical integrity of spherical agglomerates, low friability, higher quality for coating and packing and uniform particle size distribution³. Customized release profiles (sustained or extended or pulsed) can be obtained by using various polymers and preparation methods. Granulation as well as pelletization both follows the process of agglomeration, but vary a little in case of former. Agglomerates formed are irregular and 20-50% porous, whereas pellets are uniform in shape and are less porous^7,8.

Classic properties of pellets^1,9

· Amount of active ingredient needs to be maximum to attain a consistent size of pellet

· Globular and smooth surface

· 600-1000 µm is the particle size range of pellets

Advantages and disadvantages^10,11

Advantages	Disadvantages
Improved flow properties	Compressing pellets into tablets is problematic as the film coating of pellets is destroyed.
Improved appearance	Filling of pellets in a capsule is expensive
Easy dispersion and faster absorption of the drug thereby decreasing fluctuation in plasma peak	Production process is very difficult to control, since several critical process parameters such as the amount of water needed, time, pressure, etc.
Offers flexibility for designing and developing a dosage form	Required highly specialized equipments and qualified personnel
Enhanced safety and efficacy of the drug
Management of incompatible drug separation
Taste masking
Dose dumping is less susceptible
Various drugs shall be coated on pellets to activate different release rates

Recent advancement in pelletization:

Micropellet containing pellet:

In this pharmaceutical doage, pellets are prepared, wherein an inner zone consists of micropellets that are held together. The micropellets (average of diameter of 50 to 500 microns) are distributed in matrix of an excipient. The outer zone may comprise of a water insoluble polymeric coating either with or without an active ingredient¹².

Implementation of the concept of quality by design ensures reduced failure of final formulation. SeDeM Expert Diagram System (SeDeM EDS) was established to formulate tablets by means of direct compression of mixtures of drug and excipients. It gives an insight into formulation components and calculates if a composition can be directly compressed or if there is a need to add excipients before compression. Hamman et al. used SeDeM EDS as a formulation tool to formulate a multiple-unit pellet system into a tablet^12,13.

Liquisold pellets:

De Espíndola et al. are working on liquisolid pellets as a technological advancement in order to improve the solubility of poorly soluble drugs. They prepared liquisolid pellets by extrusion-spheronization with the aim of improving solubility and hence bioavailability of an antiretroviral drug, ritonavir. This formulation had the additive advantages of a multiparticulate systems along with liquisolid technology¹⁴.

Factors influencing pelletization:

Moisture content:

Water content plays an important role in determining the quality of spheres, thereby making it a significantly important process variable. A decrease in moisture content, below the lower limit would lead to production of large number of fines during the technique of spheronization. Fines may get generated with more variation in distribution of size when the moisture content is low. On the contrary, high moisture contents would lead to agglomeration of pellets, as surface of the pellets has excessive water content.

Rheology:

Rheological conditions of wet mass will determine the flowability in extruder and also during the spheronization operation. So, variation in the rheology of wet mass may result in non-uniform and improper extrusion.

Drug:

Pelletization is a versatile technique which may be used for preparation of pellet of various materials with different pattern of release mechanism (like immediate, modified). To achieve this, various process variables as well as formulation strategies have to be utilized. For example in case of poorly soluble drugs such as piroxicam, are made into an immediate release pellet using suitable excepients such as modified starch¹⁵. Pellets are used for taste masking of non-palatable drugs such as quinine sulphate¹⁶. Raval et al. prepared enteric coated pellet of budesonide, since the formulation currently available exhibit low efficacy as a result of premature drug release¹⁷. Kadam et al. prepared theophylline fast release enteric-coated pellets a chronopharmaceutic therapy as they recognized the importance of evening dosing of theophylline in treating nocturnal asthma attack¹⁸.

Composition of granulating fluid:

Pellets are prepared by a process of wet granulation, thereby making the composition and concentration of the granulating fluid an important parameter during pelletization/spheronization technique. Aqueous as well as binary mixtures of solvents are used as granulating solvents. Millili et al. reported using absolute alcohol did not yield in forming pellets successfully, while using 95% ethanol formed pellets when granulated. Though pellet formulated using water showed good granulation, but they were not very compressible¹⁹. Morkhade in his research on Itopride HCl, Atazanavir showed their tendency to produce a sticky mass when they come in contact with water. Incorporation of detackifiers was found to be ineffective. Solvents like water, isopropyl alcohol, dichloromethane, acetone and combinations were used, but without any success to produce a wet mass for pelletization. He researched a range of non-conventional solvent systems such as polyethylene glycol, poloxamers, glycerol, sodium lauryl sulphate, polysorbate 80 and triethyl citrate in combination with water. Amongst these, PEG 400 was found to be the most effective to produce a non-tacky mass suitable for pelletization²⁰.

Starting material:

Variables of starting materials such as its contents, variety, type of filler, size of particles, have a major impact on the palletization process. The rate of drug release from pellets is determined by the swelling properties of ingredients used in the manufacturing of pellets. As grades of product change the quality of pellets also fluctuate.

Spheronizer speed rate:

Speed rate of spheronizer influences density, hardness, sphericity and size of pellets. High speed of spheronizer yields high sphericity, lower friability, high crushing strength and smoother surface²¹.

Drying technique and temperature:

Ideal pellets can be obtained by adequate drying. Upon optimum drying the pellets produced will be of proper size, excellent flow and shape but this drying should be stable and reproducible for all batches. Properties such as variations in weight, inappropriate filling can alter shape, flow and size of pellets leading to alterations in the final dosage form, which may further spoil the delivery system efficiency. Wider particle size distribution can cause change in delivery dose and fluctuation in flow rate, compressibility can occur with a difference in shape³.

The screen of the extruder:

The orifice of extruder will influence the pellitization process, increase in dimensions of orifice will also increase the mean pellet size and an increase in the depth of orifice will increase the force of extrusion because of presence of water at the surface of extrudate, this increase in force of extrusion can affect the distribution and shape of pellets.

Different techniques of pelletization:

1. Layering technique

2. Cryopelletization

3. Extrusion spheronization

4. Spray drying and congealing

5. Freeze pelletization

6. Balling

Layering technique:

Layering process is the most convenient technique of pelletization. In this process, successive layers of drug are coated onto a nuclei, which may be a granule of the same material or inert starter seed. It is classified into two sub-categories:

Powder layering strategy:

In this technique, the nuclei is initially sprayed with the binder solution after which the powder is added. These nuclei are subjected to rotation in a pan where they get coated with powder particles, thereby forming layers of coating material by adhesive forces. Capillary forces developed in the liquid phase help in adhesion of these particles to the nuclei. Successive spraying is done until desirable size of pellet is obtained. Upon drying, the binder and dissolved substances crystallize out around the nuclei. The sprayed binding liquid forms liquid bridges between the nuclei/starter seed and the drug particles. These bridges on drying, eventually form solid bridges^22,23.

Solution/ suspension layer:

In this technique, the drug particles and other ingredients are dissolved in a suitable solvent. This solution or suspension is then coated evenly on the nuclei by spraying. This is followed by drying process. The dissolved material crystallizes to form solid bridge between the inner core material and the spray coated particles. This procedure is continued until the suitable layer of drug is coated on the inner core nuclei²⁴.

Cryopelletization:

In cryopelletization, liquid nitrogen in used as a solidifying medium. In this process, the drug solution/suspension in a suitable solvent is exposed to an atmosphere of liquid nitrogen at -196 °C. Rapid heat transfer between the drug solution and liquid nitrogen will permit the material to freeze. The volume of nitrogen needed for preparing the pellet depends upon temperature and solid ingredients of the suspension/solution being handled. The instrument comprised of a perforated plate through which the drug suspension is passed and introduced into an atmosphere of liquid nitrogen below. This leads to instantaneous freezing of particles. The frozen pellets are then stored at -600 °C before drying²⁵.

Extrusion spheronization²⁶:

In the mid-1960s extrusion, spheronization was developed as a method for pelletization. Extrusion spheronization method is regularly utilized in pharmaceutical business for the production of evenly sized pellets. Extrusion-spheronisation is a granulation process which produces dense pellets of high sphericity and have narrow size distribution²⁷. There are multiple steps associated in this technique. Fig.1 represents a schematic diagram of the woking steps involved. This method is helpful for producing granules with improved drug loading without forming excessively larger particles. This can also be utilized for obtaining oral controlled release dosage forms with the consumption of less quantity of excipients²⁸. Patel et al. discussed about enteric coated pellets that were prepared by a technique of extrusion and spheronization. Apart from this, an important aspect of extrusion spheronization technique while preparing pellets of poorly soluble drug is choosing the right excipients²⁹. Afrasiabi Garekani et al. studied the impact of superdisintegrant as well as polyethylene glycol (PEG) on dissolution rate of simvastatin pellets³⁰. Microcrystalline cellulose is a commonly used excipient for extrusion spheronization process. A disadvantage is reduction in the dissolution rate of drugs. This was overcome by incorporation of superdisintegrants and PEG. PEG has shown to impact the dissolution pattern of simvastatin which was the rationale for incorporation of PEG.

Fig 1. Schematic representation of extrusion spheronization technique.

Advantages of extrusion spheronization:

Extrusion-spheronization over other techniques includes following advantages:

1. High drug loading

2. Incorporation of more than one active ingredient in any required ratio

3. Physical properties of drug and excipients can be modified

4. Spherical and smooth surfaced particles

5. Spheres having smooth surface are a perfect base to apply the coating

6. Enhanced flow properties

7. Low hygroscopicity of particles

8. Evenly sized particles

9. Higher desnity particles

10. Packaging of the spheres in capsules or bigger packages is convenient compared to other dosage forms like powders.

11. Controlled drug delivery can be achieved by using suitable coating material

12. Production of fines and dust is lowered

13. Spheronization can improve the hardness and decreases granules friability based on the surface properties and adhesive forces

Extrusion spheronization consists of the following steps²⁸:

i. Process of dry blending:

Dry blending/mixing for all components is made to produce a mixture of uniformly blended powder utilizing distinctive kinds of blenders such as a high shear blender, planetary blender, twin shell blender, and tumbler blender.

ii. Process of wet massing/ granulation:

Wet massing of dry powder is done to obtain an adequate dense mass for the extrusion process. This process is the same as a customary wet granulation³¹. Generally utilized granulators are a planetary blender or the sigma cutting edge blender. Frequently planetary blender is utilized commonly for both mixing and as well as granulation activity. It is necessary to maintain the rate of evaporation of the granulating fluid, especially in case of organic solvents which tend to volatilize easily. While using high shear blender, a large quantity of energy is generated which gets transferred into the wet mass. This could result in evaporation of granulation liquid. As a precautionary step,the granulation bowl is cooled to avoid loss of solvent by evaporation³¹. The nature of binder and granulation fluid has a significant effect on physical properties as well as release kinetics of drug from pellets prepared by extrusion/spheronization. Zoubari et al., studied the effect of binder (water-soluble or insoluble) and granulating fluid (aqueous or organic) on the physical properties of pellet as well as the release kinetics of the active ingredient³².

Process of extrusion:

The mass obtained after wet granulation is subjected to pressure until the mass begins to flow. Once the mass begins to flow, it is passed through an orifice to form extrudates. The length or shape of the extrudate is determined by the geometry of the orifice, the nature of materials and the method of extrusion. The extrudate should have sufficient plasticity to turn and twist. Extrusion is carried out using either of four classes of extruders: screw, sieve and basket, roll, and ram extruders.

i. Screw type extruders:

A screw type arrangement is utilized to create sufficient pressure to make the material flow through uniform orifice. A screen is placed at the end of the screw either perpendicular to the axis of the screw or a screen is placed around the screw, wherein the extrudate falls perpendicular to the axis of the screw.

Amidst the current technology, hot melt extrusion (HME) consists of a barrel having one or two rotating screws that carry materials down the barrel. Heat as well as pressure is applied to melt the polymer, while the screws ensure homogenized mixing. Pharmaceutical preparations are suitably prepared using twin screw excruders as the two screws ensure homogenized mixing and the shear force leads to formation of finely divided solid particles³³.

ii. Sieve and basket extruder:

The wet mass is fed into a extrusion chamber by either a screw or under gravity. A rotating or oscillating device moves the mass through screen. The difference between a sieve and basket extruder is the extrudate falls vertically from the sieve plate in a sieve extruder, while in a basket extruder the extrudate is formed in the horizontal plane²⁸.

iii. Roll extruders:

Roll extruders function by feeding the wet mass between a roller and a perforated plate. They are further classified into three types. The first type consists of a ring which rotates around roller that is fixed within a cylindrical chamber. They both rotate individually along their axis. The second type of roll extruder consists of the roller placed on the outer side of the ring while the material is fed from a hopper in between the roller and the die. The third type consists of a flat stationery die plate on which the rollers are placed and allowed to roll²⁸.

iv. Ram extruder:

In a ram extruder, a piston is used to move the wet mass across the barrel and pass through the screen at the end. Ram extrusion is prevalent in laboratory scale development stages since it allows small amounts of material under tested²⁷. Zhang et al. investigated on the used of non-aqueous cellulose-based preparation using ram and lab scale roller screen extruder. They observed that non-aqueous solvents are not unsuitable for softening microcrystalline cellulose, which is a commonly used excipient in extrusion spheronization process²⁷.

Process of spheronization:

Nakahara first presented the spheronization innovation in 1964. The extrudate is broken up into smaller cylinders with a length equal to their diameter. Spheronization has three phases. It comprises of cutting the cylindrical segments of extrudate, agglomeration of broken segments and smoothing. Interaction of extrudate with the stationary wall and rotating plates breaks the cylindrical segments of extrudates. The agglomerate’s dimension is determined, followed by formation of uniformly sized spheres.

A spheronizer is a device made up of a vertical hollow cylinder and a horizontal rotating disk/friction plate within the cylinder. Extrudates on rotating plate were broken into short segments with friction plate, due to collisions between particles and also with the wall. Spinning friction plate transfers the mechanical energy into kinetic energy to form a mechanically fluidized bed. Extrudate upon further processing will attain a spherical shape. Frictional forces increases owing to the grooved surface present on the friction plate. These grooves exist in two types of arrangement. One of the arrangement shows a cross-hatch geometry wherein the grooves form right angles while the other arrangement shows a radial geometry where the pattern is radial.

Drying process:

Drying stage is required to obtain moisture content of required level in pellets. Pellets are dried at the room temperature or elevated temperatures. Equipment such as the FBD, tray driers, ovens are utilized for this purpose. Researchers examined the impact of drying method on the physical appearance and compaction qualities of spheronized granules of propyl gallate/MCC/water glue. Drying by the oven, delivered uneven and hard granules because of the improper wet powders shrinkage.

Screening process:

Screening is an important process in order to obtain an particles with a uniform size distribution. Sieves of different mesh sizes are utilized. In case pellets are produced by spheronization followed by extrusion, screening is mandatory so as to stay away from pellets having higher polydispersity.

Spray drying and congealing²⁸:

Spray drying process:

The drug suspension/solution is atomized into fine droplets with or without the addition of excipients, which is exposed radially to a moving steam of hot gas. The temperature of the droplets is immediately increased and fine droplets get dried, forming spherical particles.

Spray congealing process:

This procedure involves formation of spherical particles by introduction of molten liquid containing drug particles which is sprayed into a cooling chamber having air at lowered temperature.

Cryo pelletization:

In cryo-pelletization, pellets are produced by freeze drying. Drug in suspension/solution/emulsion are frozen by subjecting them to a stream of liquid nitrogen. The frozen droplets are then lyophyllised to obtain pellets. Rapid heat transfer between the droplets and liquid mitrogen results in the material getting immediately and uniformly frozen. Formulation related variables such as viscosity, surface tension and solid content influences droplet formation which is a critical step in cryo-pelletization²⁵.

Balling technique:

Balling also known as spherical agglomeration is a technique in which physical mixtures of drug and excipients are converted into spherical pellets by constant tumbling or rolling motion. Balling can be categorised into 2 types: liquid induced agglomerations and melt induced agglomerations. Balling is popularly used in fertilizer or iron ore industries, while its pharmaceutical applications are limited. In liquid induced agglomeration, liquid is introduced into the powder during or before the agggitation step. Agglomerates or nuclei are formed when powder comes in contact with the liquid phase. Melt induced agglomeration is similar to that of liquid incuded agglomeration except that here the binding material is a melt. Formulation variables such as particle size, solubility, extent of liquid saturation and viscosity of liquid phase influence the rate and extent of agglomeration²⁸.

Assessment of pellets^24,28,34-36:

Drug content

It can help to determine the concentration of drug in pellets. The concentration of drug can be determined with the help of suitable UV method or HPLC method or some other suitable analytical methods^37-39.

Distribution of size:

Pellets sizing is mandatory as it has a high impact on the release rate kinetics. Generally, determination of particle size is done by sieve analysis or microscopic techniques. Parameter such as the diameter of geometric mean length, and width of particle mean, ferret diameter mean applies for the determination of the distribution of particle size^40,41.

The shape of pellets:

There are different methods to determine the sphericity of pellets and it is very important to determine it. Determination of the deviations of the spherical geometry from a circular zone is made by the shape factor. It is determined by means of pellets projected area and their circumference. Shape factor value 1 gives perfect circular pellets projection and value of 0.6 gives good sphericity. Shape factor or roundness index must be within 1-1.2 for obtaining acceptable pellet quality. Visual examination of the pellets using stereo-microscope and light microscope is another way to decide pellets shape. Another common method is through an angle of repose to measure the flow property and pellets circularity. In this, the proportion of height produced by a heap of pellets is measured and radius is calculated by using fixed funnel. Certain amount of pellets allowed to fall from the measured height through the orifice following which the heap height and the radius is measured⁴¹.

Morphology of structure:

Morphology of pellets is examined using SEM (Scanning electron microscope). Optical microscope was used for examining pellets surface microstructures. The roughness of structure can be studied using non-contracting profile laser meters^41-43.

Surface area:

The surface area of pellets is controlled by the particle size, shape, porosity and roughness of pellet. It is an important parameter that has an impact on release rate of drug from the pellets^40,42,43.

Friability:

Various process of pelletization may impact the properties of pellets. It may get chipped and result in formation of dust while coating and handling. Lower friability of pellets is required for subsequent coating. Turbula and erweka are the types of apparatus used for the determination of pellets friability^41,44.

Pellets porosity:

Porosity impacts the drug release from pellets as it affects drug dissolution characteristics. Mercury porosimetry can be used for quantitatively estimating pellets porosity⁴⁵.

Tensile strength measurement

The tensile strength of pellets is usful to measure the load require to break the pellets. This is a measure of hardness of pellets^46,47.

Disintegration time:

Disintegration time is one of the important test to measure the disintegration of pellets. This test is usually performed in 0.1 N HCl⁴⁵.

In vitro dissolution studies:

Commonly it is performed using USP Type-1 and USP Type-2 apparatus. They help to determine drug release pattern from the pellets^41,48.

Summary and conclusion:

This review focused on pelletization and technique of pelletization to produce spherical pellets. Every technique comes with advantages and disadvantages. For instance, extrusion spheronization is a widely used method for producing spherical pellets that elicit high drug loading, but a major setback is that it consumes granulating liquid such as an aqueous system which requires drying which is a time consuming process. Several drugs are affected due to the presence of water. To overcome the disadvantage associated with extrusion spheronization technique, cryopelletization was developed as a novel pelletization technique. This involves freeze-drying or lyophilization in order to remove water or any solvents. A drawback of this method is its requirement for liquid nitrogen that has a temperature of -196°C. When liquid droplets comes in contact with liquid nitrogen, it creates surface irregularities in pellets. Sudden freezing at a low temperature leads to formation of highly porous particles. A hot-melt extrusion process yields spherical pellets. It is a continuous process and does not essentially involve the use of water or solvents. This method is advantageous when drug shows instability in presence of water. Freeze pelletization technique is cost effective, since there are lesser steps and less process variables. The technique produces spherical shaped pellets with narrow size distribution at room temperature. In the present scenario, pelletization has gained importance in novel drug delivery. The scope for development of different modified release solid oral dosage forms widened with technological advancements in pelletization.

CONFLICT OF INTEREST:

All authors (Kishore Manoharan, Navya Ajitkumar Bhaskaran and Lalit Kumar) declare that they don’t have any conflict of interest.

Statement of human and animal rights:

This article does not comprise any study with human and animal subjects.

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Received on 14.06.2019 Modified on 26.07.2019

Research J. Pharm. and Tech. 2019; 12(12): 6157-6164.

DOI: 10.5958/0974-360X.2019.01070.9