pelletisation technique and extrusion … · 2020. 12. 17. · because pellets disperse freely in...

Shramika A. Chore And S. J. Dighade., Pelletisation technique

International Research Journal of Pharmaceutical and Biosciences (IRJPBS) 5 (6) 1

REVIEW ARTICLE

International Research Journal of Pharmaceutical and Biosciences

Pri-ISSN: 2394 -5826 http://www.irjpbs.come-ISSN: 2394 - 5834

PELLETISATION TECHNIQUE AND EXTRUSION-SPHERONISATION: A LITERATURE REVIEW

Shramika A. Chore*1, S. J. Dighade2

1 Department of Pharmaceutics, Institute of Pharmacy and Research, Badnera- Amravati, Maharashtra, India

2 Departments of Pharmaceutical Chemistry, Institute of Pharmacy and Research, Badnera-Amravati, Maharashtra, India

Article info Abstract

Article history:

Received 27 NOV 2020

Accepted 05 DEC 2020

*Corresponding author:

[email protected]

Copyright © 2020irjpbs

ABSTRACT: There are different pelletizations and granulation techniques

available to prepare drug loaded spherical particles or granules. Extrusion

Spheronization is one of them and utilized in formulation of beads and

pellets. Limitations related to bioavailability and site specific drug delivery

can be overcome by this technique. Extrusion spheronization is widely

applied method for the production of multi particulates, like pellets and

beads, for the oral controlled drug delivery system. Pelletization

technique enables the formation of spherical beads pellets with a means

diameter usually ranging from 0.5-2.0 mm which can be eventually coated

for preparation of modified release dosage form. Today this technology

has gained attention because of its simple and fast processing. Extrusion

spheronization is widely utilized in formulation of sustained release,

controlled release delivery system. This article discusses about the

extrusion spheronization process and its application in pharmaceutical

industry as well as focuses on modified process called as melt extrusion

process utilized for formulation of sustained release tablets, trans dermal

delivery system and trans mucosal delivery system in pharmaceutical

industry.

Keywords: Spheronization, Pellets, Extrusion, Powder Layering.



INTRODUCTION

The drugs administered by oral route are versatile, flexible in dosage strength, relatively stable,

present lesser problem in formulation and packaging and are convenient to manufacturer,

store, handle and use. Solid dosage forms provide best protection to drugs against

temperature, light, oxygen and stress during transportation. As a drug entity nears the end of

its patent life, it is common for pharmaceutical manufacturers to develop a given drug entity in

a new and improved dosage form.[1,3] Drug delivery systems (DDS) are a strategic tool for

expanding markets/ indications, extending product life cycles and generating opportunities.

Oral administration is the most popular route for systemic effects due to its ease of ingestion,

pain, avoidance, versatility and most importantly, patient compliance. Tablet/Pellets are the

most popular among all dosage forms existing today because of its convenience of self-

administration, compactness and easy manufacturing, however in many cases immediate onset

of action is required than conventional therapy. Immediate release solid oral dosage forms are

classified as either having rapid or slow dissolution rates. Immediate release dosage forms are

those for which ≥85% of labelled amount dissolves within 30 min. Disintegrating agents are

substances routinely included in tablet formulations and in some hard shell capsule

formulations to promote moisture penetration and dispersion of the matrix of the dosage form

in dissolution fluids.[1,2]

HISTORY OF PELLETS

The term pellets has been used by a number of industry to describe a variety of agglomerates

produced from diverse raw materials, using different pieces of manufacturing equipment.

These agglomerates include fertilizer, animal feeds, iron ores and pharmaceutical dosage unit

and thus do not only differ in composition but also encompass different things for different

industries. When it becomes to pharmaceutical industry, it was only in the early 1950’s, in

response to a desire to sustain the release of drug over an extended period of time, that the

pharmaceutical industry developed a keen interest in the technology. And it’s been since the

late 1970’s the advantages of pellets over single unit dosage forms have been realized. In time,

extensive research was conducted to develop pelletization techniques and major resources

were allocated towards exploring method that were faster, cheaper and more efficient both in

terms of formulation and processing equipment.[4]

Pellets have to meet the following requirements [4]

(1) They should be near spherical and have a smooth surface; both considered optimum

characteristics for subsequent film coating.

(2) The particle size range should be as narrow as possible. The optimum size of pellets for

pharmaceutical use is considered to be between 600 and 1000 µm.



(3) The pellets should contain as much as possible of the active ingredient to keep the size of

the final dosage form within reasonable limits.

In the last two decades, pellets have established their position in pharmaceutical dosage for

many reasons. Pellets offer a great flexibility in pharmaceutical solid dosage form design and

development. They flow freely and pack easily without significant difficulties, resulting in

uniform and reproducible fill weight of capsules and tablets. Successful film coating can be

applied onto pellets due to their ideal spherical shape and a low surface area-to-volume ratio.

Pellets composed of different drugs blended and formulated in a single dosage form. This

approach facilitates the delivery of two or more drugs, chemically compatible or incompatible,

at the same sites or different sites in the gastrointestinal tract. Even pellets with different

release rates of the same drug can be supplied in a single dosage form. The pelletized products

can improve the safety and efficacy of the active agent. These multiple-unit dosages are usually

formulated in the form of suspensions, capsules or disintegrating tablets, showing a number of

advantages over the single-unit dosage system. The pelletized product can freely disperse in the

gastrointestinal tract as a subunit, thus maximizing drug absorption and reducing peak plasma

fluctuation. Consequently, potential side effects can be minimized without impairing drug

bioavailability. Local irritation attributed to high local concentrations of a drug from a single-

unit dose, can be avoided.[5]

The most important reason for the wide acceptance of multiple-unit products is the rapid

increase in popularity of oral controlled-release dosage forms. Controlled release oral solid

dosage forms are usually intended either for delivery of the drug at a specific site within the

gastrointestinal tract or to sustain the action of drugs over an extended period of time. With

pellets, the above mentioned goals can be obtained through the application of coating

materials (mainly different polymers), providing the desired function, or through the

formulation of matrix pellets to provide the desired effect. It has been reported that pellets

smaller than about 2.4 mm in diameter, are free from the digestive function of the stomach and

the closing system of the pyloric sphincter to be emptied from the stomach. A maximum pellet

diameter of 1.5 mm has been recommended for an optimal multiple-unit formulation. Kelly

1981 and Devereux 1987 clearly showed that the threshold size must be below 1 mm.

According to Khosla et al., (1989), there is no actual cut-off size for gastric emptying, but as the

size of the pellets increase, predictable emptying from the fed stomach becomes uncertain

and highly variable. However, it has been demonstrated that gastric emptying is not only

dependent on the size but also on some other important factors, such as density of pellets and

inter-subject variation. Clarke et al. 1993 and Tuleu et al., 1999 showed that both density and

size of the pellets affect the gastrointestinal transit time. The higher density of the pellets

prolonged the gastric transit time, while the larger size slightly prolonged the small gut transit

time but not the gastric transit time. Controversial results have also been reported to the effect

of pellets densities on the transit times through the gastrointestinal tract.[4,5]



RATIONALE FOR PELLETIZATION [6,7]

Pellets are of great interest to the pharmaceutical industry for a variety of reasons.

Pelletized products not only offer flexibility in dosage form design and development, but are

also utilized to improve safety and efficacy of bioactive agents. However, the single most

important factor responsible for the proliferation of pelletized products is the popularity of

controlled release technology in the delivery of drugs.

When pellets containing the active ingredient are administered in vivo in the form of

suspensions, capsules, or disintegrating tablets, they offer significant therapeutic advantages

over single unit dosage forms. Because pellets disperse freely in the gastrointestinal tract,

they invariably maximize drug absorption , reduce peak plasma fluctuations ,and minimize

potential side effects without appreciably lowering drug bioavailability .Pellets also reduce

variations in gastric emptying rates and overall transit times. Thus, intra – and inter – subject

variability of plasma profiles, which are common with single-unit dosage regimens, are

minimized. Another advantage of pellets over single-unit dosage forms is that high local

concentrations of bioactive agents, which may inherently be irritative or anesthetic, can be

avoided. When formulated as modified – release dosage forms, pellets are less susceptible to

dose dumping than the reservoir - type, single-unit formulations.

Controlled release pellets are manufactured either to deliver the bioactive agent at a

specific site within the gastrointestinal tract or to sustain the action of drugs over an

extended period of time. While these results have been traditionally achieved through the

application of a functional coating material, at times the core pellets themselves have been

modified to provide the desired effect.

Advantages of Pelletization [7,8]

1. Pellets provide an ideal shape for application of film coating.

2. High local concentration of bioactive agents can be avoided

3. Pellets reduce variation in gastric emptying time.

4. Pellets provide tremendous flexibility in development of oral dosage form.

5. Pellets allow combined delivery of two or more bioactive agents that may not be

compatible, at the same or different sites in GI tract.

6. Pellets also permit combination of pellets of different release rates of same in a single

dosage form.

7. It helps to achieve uniform and reproducible fill weights in capsules.

8. Pellets can also be made attractive aesthetically due to various shades of colour that can be

imparted.



Theory of Pellet formation and Growth [9,10,11]

In order to judiciously select and optimize any pelletization/granulation process, it is important

to understand the fundamental mechanisms of granule formation and growth. Different

theories have been postulated related to the mechanism of formation and growth of pellets.

Some of these theories are derived from experimental results while others are confined to

visual observations. As the conventional granulation, the most thoroughly studied, most

classified pelletization process, which involves a rotating drum, a pan or a disc, has been divided

into three consecutive regions: nucleation, transition and ball growth. However, based on the

experiments carried on the mechanism of pellet formation and growth, the following steps

were proposed: nucleation, coalescence, layering and abrasion transfer.

Nucleation (Figure 3A) is a common stage in all pelletization/granulation processes and occurs

whenever a powder is wetted with liquid. The primary particles are drawn together to form

three-phase air-water-liquid nuclei and are attached together by liquid bridges which are

pendulous in nature. The bonding strength is improved by reduction of particle size. The sizes

of the primary particles, the moisture content, the viscosity of the binding particles, the

wettability of the substrate and the processing conditions, such as tumbling and drying rates,

influence the size, the rate and the extent of nuclear formation. Both the mass and the number

of nuclei in the system, change as a function of time, which is an important feature of

nucleation.

Nucleation is followed by a transition phase, and the growth mechanisms affecting the

transition region are coalescence and layering.

Coalescence (Figure 3B) is defined as the formation of large-sized particles by random collision

of well-formed nuclei, and the mechanism requires slight excess moisture on the nuclear

surface. Although the number of nuclei is progressively reduced, the total mass of the system

remains unchanged during this step.

Layering (Figure 3C) is a slow growth mechanism and involves the successive addition of

fragments and fines on an already formed nucleus. In the layering step, the number of particles

remains the same, but the total mass in the system increases due to increasing particle size as a

function of time.



Figure 1: Pellet growth mechanisms. (A) Nucleation, (B) coalescence, (C) layering and (D)

abrasion transfer.

The fragments or fine particles can be formed by particle size reduction that occurs due to

attrition, breakage and shatter. Large pellets pick up the fines and the fragments that are

produced through size reduction. Production of fines and subsequent coalescence and

layering continues until the number of favorable collisions declines rapidly, thereby leading to a

reduction in the rate of growth of the pellets. At this point the third phase, the ball growth

region, is reached. In the ball growth phase the main mechanism affecting the slow growth

of agglomeration is the abrasion transfer (Figure 1D) which involves the transfer of materials

from one granule formed to another without any preference in either direction. This situation

does not result in a change in the total number or mass of the particles. The particles, however,

undergo a continuous change in size as long as the conditions that lead to the transfer of

material exist.

One of significant properties of pellets is their ability to withstand the mechanical forces that

act on then during the manufacturing process and subsequent conditioning and or coating and

handling of the pellets. Due to lack of sufficient mechanical strength, they may disintegrate

completely or wear down in size attributed to frictional forces. It is absolutely essential;

therefore, the pellets possess sufficient strength to overcome any appreciable abrasion during

agitation.

Thus, it is essential that fundamental mechanisms of pellet formation and growth are clearly

understood in order to judiciously select and optimize any pelletization process. Various

theories that attempt to explain these mechanisms have been postulated. Some of these

theories are supported by experimental results, while others are interferences relying on visual

observations.



Immediate release dosage form [8,11]

The term “immediate release” pharmaceutical formulation includes any formulation in which

the rate of release of drug from the formulation and/or the absorption of drug, is neither

appreciably, nor intentionally, retarded by galenic manipulations.

In the present case, immediate release may be provided for by way of an appropriate

pharmaceutically acceptable diluents or carrier, which diluents or carrier does not prolong, to

an appreciable extent, the rate of drug release and/or absorption. Thus, the term excludes

formulations which are adapted to provide for “modified”, “controlled”, “sustained”,

“prolonged”, “extended” or “delayed “release of drug.

Many dosage forms are designed to release the drug immediately or at least as quickly as

possible after administration. This is useful if a fast onset of action is required for therapeutic

reasons.

For example, a tablet containing a painkiller should disintegrate quickly in the gastrointestinal

tract to allow a fast uptake into the body. The onset of action is very fast for intravenous

injections and infusions and the pharmacological effect may be seen in a matter of seconds

after administration.

The reasons for this are twofold

1. The drug is already in solution, so strictly speaking the drug does not have to be released

from the dosage form at all.

2. The drug is directly administered into the body, so no time is lost due to drug permeation

through the skin or mucosal membranes, before the target organs can be reached.

In oral solutions the drug is also already released and the solution will simply mix with the

gastrointestinal fluids. However, powders and granules need to dissolve first before the drug is

released by dissolution. For tablets it is initially necessary that the tablet disintegrates (if it is

formed from compressed granules this will initially happen to the level of the granules, from

which further disintegration into powder particles and finally drug dissolution occurs).

For capsules to release their drug content it is necessary for the capsule shell material (for

example, gelatin or hydroxypropyl methyl cellulose (HPMC)) first to disintegrate. Thereafter the

drug can either dissolve from the usually solid powders or granules in the case of hard gelatin

or HPMC capsules or it can be dispersed from the usually liquid, lipophilic content of a soft

gelatin capsule. These types of immediate-release dosage forms have an onset of action in the

order of minutes to hours. Immediate-release dosage forms usually release (dissolve or

disperse) the drug in a single action following a first-order kinetics profile.

This means the drug is released initially very quickly and then passes through the mucosal

membrane into the body, reaching the highest plasma level (termed Cmax) in a comparatively

short time (termed t max). Uptake through the mucosal membranes may be due to passive

diffusion or by receptor-mediated active transport mechanisms. Once taken up into the body

the drug is distributed throughout the body and elimination of the drug by metabolism and

excretion occurs. The elimination process also usually follows first-order kinetics. Therefore the



plasma levels measured over time after administration of an immediate-release dosage form

(the plasma concentration time curve) basically are the sum of a first-order absorption and a

first-order elimination process. Figure shows an idealized plasma concentration versus time

profile of an immediate-release oral dosage form.

Figure 2 :- Idealized plasma concentration versus time profile of an immediate release oral

dosage form. The highest drug plasma concentration is termed Cmax. The time at which Cmax is

reached is termed tmax.

An important consideration for immediate-release dosage forms is that the time of action of

the drug is limited to the time that the concentration of the drug is above the MEC. If the drug

has a short biological half-life, this time interval may be short, requiring frequent dosing and

potentially leading to low patient compliance and suboptimal therapeutic outcome.

The biological half-life of a drug is defined as the time required reducing the plasma

concentration by 50% by metabolism or excretion. Many studies show that a large proportion

of patients do not take drugs as directed (for example three times a day), especially if the

disease is (at least initially) not accompanied by strong symptoms, for example in the treatment

of high blood pressure or glaucoma. To reduce the frequency of drug administration it is often

not possible simply to increase the dose of an immediate-release dosage form as the peak

plasma concentrations may be too high and lead to unacceptable side-effects. Therefore the

drug concentration within the plasma should be above the MEC and below the MTC, i.e. within

the therapeutic range.



Figure 3 : - Drug plasma levels after oral administration of a drug from an immediate-release

dosage from. The therapeutic range is the concentration interval between the minimal

effective concentration (MEC) and the minimal toxic concentration (MTC). ∆t is the time

interval the drug is in the therapeutic range.

ADVANTAGES OF IMMEDIATE RELEASE DRUG DELIVERY SYSTEM [9,10,12]

1. Desired criteria for immediate release drug delivery system

Immediate release dosage form should:

1. In case of solid dosage it should dissolve or disintegrate in the stomach within a short period.

2. In case of liquid dosage form it should be compatible with taste masking.

3. Be portable without fragility concern.

4. Have a pleasing mouth feel.

5. It should not leave minimal or no residue in the mouth after oral administration.

6. Exhibit low sensitivity to environmental condition as humidity and temperature.

7. Be manufactured using conventional processing and packaging equipment at low cost.

8. Rapid dissolution and absorption of drug, which may produce rapid onset of action.

2. Merits immediate release drug delivery system

1. Improved compliance/added convenience

2. Improved stability, bioavailability

3. Suitable for controlled/sustained release actives.

4. Allows high drug loading.

5. Ability to provide advantages of liquid medication in the form of solid preparation.

6. Adaptable and amenable to existing processing and packaging machinery.

7. Cost- effective

8. Improved solubility of the pharmaceutical composition.

9. Decreased disintegration and dissolution times for immediate release oral dosage forms.



In Pharmaceutical industry, pellets can be defined as small, free-flowing, spherical particulates

manufactured by the agglomeration of fine powders and excipients using appropriate

processing equipment.

The general term “granulation” and “pelletization” are sometimes used synonymously, the unit

obtained are referred to as granules, pellets, agglomerates or spheroids without making any

clear distinction among them. Generally, if a size-enlargement process produces agglomerates

of a size distribution within the range of 0.1 mm to 2.0 mm and a high porosity ( about 20-

50%),the process may be called “granulates”. “pelletization” is often referred to as a size-

enlargement process that involves the manufacture of agglomerates with a relatively narrow

size range ,usually with mean size from 0.25 to 2.0 mm, named “pellets”. Pellets have free-

flowing properties and a low porosity (about 10%).[8]

The term “spheronization” is usually associated with spherical unit formed by a special process

that includes a spheronization step where extrudates or agglomerates are rounded as they

tumble on a rotating frictional base plate.

Pelletization is one of the most promising techniques for the multi particulate drug delivery

system. The interest in pellets as dosage forms (filled into hard gelatin capsule or compressed

into disintegrating tablet) has been increasing continuously, since their multi particulate nature

offers many important pharmacological as well as technological advantages over conventional

single-unit solid dosage forms. They can be divided into desired dose strengths without

formulation or process changes and also can be blended to delivery incompatible bioactive

agent simultaneously and/orto provide different sites in the gastrointestinal (GI) tract. When

taken orally, they disperse freely in the GI tract, maximize drug absorption, minimize local

irritation of the mucosa by certain irritant drugs, and reduce inter- and intra-patient variability.

Because of these enormous advantages, pelletization has become focus of extensive research,

on refining & optimizing the existing techniques, as well as on the development of novel

manufacturing approaches.[11]

Advantages & limitation [12,13,14]

Pellets offer a significant number of advantages over conventional unit –dose system.

Technological advantages

1.Uniformity of dose

Layering techniques and extrusion spheronization technique offer great accuracy with uniform

drug delivery to the pellets.

2. Sphere have excellent flow properties. This becomes very useful in automated processes or

in processes or in processes where exact dosing is required, e.g. tableting, moulding operation,

capsule filling and packaging.



3. Prevention of dust formation, resulting in an improvement of the process safety, as fine

powders can cause dust explosions and the respiration of fines can cause health problems.

4. Controlled release application of pellets due to the ideal low surface area-to-column ratio

that provides an ideal shape for the application of film coating.

5. They can be blended to deliver incompatible bioactive agent simultaneously and/or to

provide different release profile at the same or different sites in the GIT.

Therapeutics advantages

1. Pellets can disperde freely throughout the GIT after administration and consequently the

drug absorption is maximized.

2. The wide distribution of spherical particles in the GIT limits localized build-up of the drug,

avoiding the irritant effect of some drug on the gastric mucosa.

3. Reduce inter-and intra-patient variability.

4. Modified-release multiparticulate delivery systems are less susceptible to dose dumping than

single-unit doasge forms.

Disadvantage

1. It is difficult to compress pellets into tablet as they are too rigid. Therefore, they are often

delivered encapsulated in hard gelatine shells.

2. Pelletization demands highly sophisticated and specialized equipment,thereby increasing the

cost of manufacturing.

3.The control of manufacturing process is complicated with too many process variables as well

as formulation variables.

Pelletization Techniques [15,16]

The most commonly used and intensively investigated pelletization techniques include

extrusion-spheronization, powder layering and solution suspension layering. There are other

method available which can be used for preparing pellets .



Figure 4 : Different techniques of Pelletization

Extrusion-spheronisation [17,18,19,20]

Extrusion /spheronization is a multistage process for obtaining pellets with uniform size from

wet granulates (extrudates). The method involves the following main steps.

• The dry mixing of the ingerdient, in order to achive homogenous powder dispersion;

• Wet massing in which the powders are wet mixed to form a sufficient plastic mass.

• An extrusion stage, in which the wet mass is shaped into cylindrical segment with a

uniform diameter;

• The spheronisation stage,in which the small cylendrical are rolled into solid spheres

( spheroids)

• The drying of the spheroids,in order to achive the desired final moisture content.

• Screening (optional), to achive the desired narrow size distribution.

Pelletization

Agitation Compaction Layering Globulation

Balling Compression

Extrusion /

Spheronization

Powder

Solution /

Suspension

Spray

drying

Spray

congealing



Figure 5 : Process of Extrusion-Spheronization

Extrusion

In extrusion wet mass is shaped into cylindrical segments with a uniform diameter. This stage

forms an integral part of overall spheronization process and is the major contributing factor in

the final particle size of pellets, the diameter being directly controlled by diameter of extruder

screen.

It consist in applying pressure to a wet mass until it passes through the calibrated opening of a

screen or die plate of the extruder and further shaped into small extrudate. the extrudate must

have enough plasticity in order to deform,but an exxessive plasticity may lead to extrudates

which stick to each other. The diameter of the segment and the final size of the spheroids

depends on the diameter of the openings in the extruder screen.

To produce an extrusion the wet mass has to be raised to a pressure sufficient for it to undergo

plastic deformation and flow through a die (the cylindrical hole of the extruder screen). If this

were the only requirement the process would be simple - requiring high levels of moisture and

low pressures.

However, the subsequent Spheronization process requires the extrusion to be friable enough to

break into short lengths, sufficiently plastic for these short lengths to form into spheres and not

so wet that the spheres agglomerate and become oversize. These are conflicting requirements

which are rendered compatible by careful formulation and by choice of suitable characteristics

in the Extruder.



Fig 6: Axial- Screw Feed Extruder Fig 7: Rotary Cylinder Extruder

Fig 8: Radial-Screw feed Extruder Fig 9: Radial gear Extruder

Fig 10: Ram Extruder



Spheronization

It refers to the formation of spherical particles from the small rods produced by extrusion. The

essential part of the spheronizer is the friction plate. The indentation pattern on the plate can

have various designs, which correspond to specific purposes. The most common design is the

cross-hatch pattern with grooves intersecting each other at 90˚ angles.

In order to form spheroid,the extrudates are brought onto the rotating friction plate of the

spheronizer, which imparts a rolling motion to the materials. Following the collisions between

the extrudates with each other and with the friction plate and the stationary walls of the

spheronization chamber, the cylindrical segments to spheres durng the spheronization process

occurs in several stage.

Extrusion/spheronization is a versatile process for producing pellets with useful properties.

Microcrystalline cellulose (MCC) is extensively used for preparing the above mentioned ‘wet

mass’ from which the pellets are to be prepared. MCC is considered as golden standard for

extrusion-spheronization. Based on its good binding properties, it is able to provide the

appropriate rhenological movement of water through the plastic mass. It prevents phase

separation during extrusion or spheronization. However ,some limitation of MCC as exxipients

for production of pellets by spheronisation has been reported in various literature.

• Drug adsorption onto the surface of MCC fibres has been reported.

• Chemical incompatibility of MCC eith a number of drugs.

• Lack of disintegration of MCC based pellets was reported in some literatures.

Figure 11 : In process pellets motion



Fig12: Schematic representation of a spheronizer friction plate with a cross-hatch patterns

indentation

Fig 13: Shape Transition during a spheronization process

Principle variables affecting Pellet Quality

Given a viable formulation, pellet quality depends upon the following three variables:-

* Load

-Too little and the pellets loose the interactive forces which help them to round.

-Too much and the roping action will be lost and too much work put into a small proportion of

the load - pellet quality suffers.

* Speed

-Too fast and the Spheronizer will create dust (if the extrusions are too wet the forming pellets

may agglomerate or stick to the wheel)

-Too slow and the process will take longer than necessary or the pellets not achieve roundness.



* Time

-Too short and the pellets will not be round

-Too long and the pellets may grow too large or dry out resulting in dusting or

breakage of some pellets. Whether or not pellet equality suffers the production rate is reduced.

However, with a robust formulation any one of these three parameters may be varied 25% or

more without serious effect. Good Spheronization is a very stable process.

Hot Melt Extrusion [18]

This is a newly modified variation of extrusion-spheronization method. Here a drug substance

and excipients are converted into a molten or semi-moletn state and subsequentlyshaped using

appropriate equipment to provide solid sphere or pellets. This is a simple,efficent and

contiuous process which requires fewer processing stages. It dose not involve addition of water

or other solvent, in disparity to granulation process.

Layering Techniques [19]

Solution & Suspension layering

Layering a solution/suspension of a drug on a ‘starter seed’ material ( usually, a coarse crystal

or nonpareil) can produce pellets that are uniform in size distribution and generally possess

very goog surface morphology. These characteristics are especially desirable when pellets will

be coated for the purpose of achieving a controlled release.

The wurster coating process,which was invented about 30 years ago, had evolved through

elaborated design modification and refinement into ideal equipment for the manufacture of

pellets by solution and suspension layering. The primary features that distinguish wruster

equipment from other fluid-bed equipment are the cylendrical partition located in the product

chamber and the configuration of the air distributor plate, also known as the orifice plate. This

plate is configured to allow most of the fluidization or drying air distributor plate, also known as

the orifice plate. This plate is configured to allow most of the fluidization or drying air to pass at

high velocity around the nozzel and through the partition ,carrying with it the particles to the

expansion chamber. In the large expansion chamber,the velocity of air becomes slower,

thereby causing the partition. The down bed is kept aerated by the small fraction of air that

passes through the small holes on the periphery of the orifice plate . the particles in the down

bed are transported horizontally through the gap between the air distributor plate and the

partition by suction generated by the high air velocity that prevails around the nozzle and

immediately below the partition. Thus, a constant and well-organised motion of particles is

formed inside the chamber, helping a uniform coating on the particle to form.

The importance of various process parameter are very high while layering with wruster

technique. It is important to identify and optimize various formulation characteristics like

solubility, concentration of binder, viscosity of solution/suspension etc. when suspension are

used ,the size of particles must be very carefully optimized as smooth and potent pellets that



can only be obtained by using small (micron-sized) particles, otherwise the surface of pellets

tend to be rough, which may adversely affect the coating process.

Solution /suspension layering is usually used when the desired drug loading of the pellets is low

because production of high-potency pellets from a low solid content formulation is not

economically feasible. In case of suspension, another important factor comes into play i.e. the

particle size of the drug. Micronized drug particle provide smooth pellets, and therefore are

preferable for controlled- release formulation where subsequent film coating is required. A

drug with larger particle size require higher amount of binder solution. As a result, potency of

prepared pellets is reduced and their surface also tend to be rough.

Figure 14 : Principle of solution / suspension layering

Powder Layering [17]

In powder layering liquid saturation is low and irrespective of the solubility of the drug in the

binding liquid, complete dissolution does not occur. Typically, a binder solution is first sprayed

onto the nuclei, followed by the addition of powder. The most nuclei tumble in the rotating pan

of disc, pick up powder particles, and form layers of small particles that adhere to each other

and the nuclei by means of capillary forces developed in the liquid phase. As additional

bonding, liquid is sprayed, layering of more powder on the nuclei continues until the

desired pellet sizes are obtained. On drying, the binder and other dissolved substance

crystallize out and the liquid bridges are partially replaced by solid bridges. On spraying with

binder, fines may pick up moisture and enter a nucleation phase. These nuclei then act as

starter seeds rather than entering into a layer surrounding the original nuclei. Powder layering

process may be intermittent or continuous. In an intermittent process, the layering solution is

added until the bed is wet and tacky. The drug powder is then added until the bed is dry. Warm

drying air may be used after each cycle. The process continues until all of the powder has been

added. In a continuous process, the layering solution and drug powder are added

simultaneously.



Figure 15 : Principle of Powder layering

Balling [19,20]

Balling or Spherical agglomeration is a pelletization process in which powders, upon addition of

an appropriate quantity of liquid, are converted to spherical particles by a continuous rolling or

tumbling action. The liquid may be added prior to or during the agitation stage. Over the years,

balling has been carried out in horizontal drum. As powders come in contact with a liquid

phase, they form agglomerates or nuclei which initially are bound together by liquid bridges

that are subsequently replaced by solid bridges derived from the hardening binder or any

other dissolved material within the liquid phase. The nuclei formed collide with other nuclei

and coalescence to form larger nuclei or pellets. The coalescence process continues until a

condition arises where the bonding forces are overcome by the breaking forces. At this

point, coalescence is replaced by the layering process where small particles adhere to much

larger particles and increase the size of the latter until pelletization is completed.

Simultaneously, particles undergo nucleation and coalescence to form differently sized nuclei

admixed with the larger pellets. As a result, balling tends to produce pellets with a wide particle

size distribution. By contrast, the technique has not been popular in the pharmaceutical

industry as a pellet process, probably due to the constraints of particle size distribution and

content uniformity. It is appropriate, therefore, to examine the various phases of pellet growth

in a drum, pan, or disc pelletizer.

Compression [20]

compression is one of type of compaction technique for preparing pellets. Pellets of definite

sizes and shapes are prepared by compaction mixture or blend of active ingredients and

exipients under pressure.0 The formulation and process variable controlling the quality of

pellets prepared are similar to those used in tablet manufactring.



Globulation [20]

Globuation or droplet formation consist of two related processes, spray drying and spray

congealing. They involve atomization of hot melts, solution or suspension to generate spherical

particle or pellets.

Spray Drying [21,22]

During spray drying, drug entities in solution or suspension are sprayed with or without

excipients into a hot stream of air to generates dry and highly spherical particles. As the

atomized droplet come in contacty with hot air, evaporation of the application medium occurs.

This drying process continues through a series of stages whereby the viscosity of the droplet

constantly increase until finally almost the entire application medium is evaporated and solid

particle are obtained. Though the technique is suitable for the development of controlled-

release pellets, it is generally employed to improve the dissolution rates and the bioavailability

of poorly soluble drug. Also, this method is applied for processing heat sensitive

pharmaceuticals, such as amino acid, antibiotics, ascorbic acid, liver extracts, pepsin and similar

enzymes. The spray-dried powder particles are homogenous, approximately spherical and

nearly uniform in size.

Spray congealing [21,22]

Spray-congealing is a process in which a drug is allowed to melt,disperse or dissolve in hot

melts of gums,waxes,fatty acid or other melting solid. The dispersion is then sprayed into a

stream of air and other gases with a temperature below the melting point of the formulation

components. Under appropriate processing conditions, spherical congealed pellets are

obtained.

Cryopelletization [21,22]

Cryopelletization is a process whereby droplet of a liquid formulation are converted into solid

spherical particles or pellets by using liquid nitrogen as the fixing medium at 160˚c. The

procedure permits instantaneous and uniform freezing of the material. The rapid heat transfer

that occurs between the droplet and liqiud nitrogen is responsible for the same. The pellets are

dried in conventional freeze dryers. Generally, 3-5 kg of liquid nitrogen is required for

preparation of 1 kg pellets.

Most pellet formulations on the market and most studies of this process are based on the use

of microcrystalline cellulose (MCC) as a spheronization agent to ensure the process functions

well. However, MCC cannot provide a formulation for all drugs. For many drugs, it is also not

possible to incorporate high-drug doses into MCC pellets. Even when pellets can be prepared,

there could be problems regarding chemical instability of the drug, as reported, for example,

for Ranitidine. A disadvantage of using MCC is the high costs of the material, especially as large

quantities of at least 50% w/w or more are required in a formulation, which also restrict the

maximum dose of drug that can be incorporated to ensure a reasonably small size of a capsule



or a tablet. For the formulations to extrude and change shape during the spheronization

process, it is necessary to add larger amounts of liquid binder to achieve a plastic wet mass. The

liquid binder is preferably water or a mixture of water with ethanol, glycerol or self-emulsifying

systems.

One approach to provide alternative excipients to aid the process of extrusion/ spheronization

has been the modification of the standard grades of MCC by co-processing the wet cake with

hydrophilic polymers such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC) or

sodium carboxymethylcellulose;the latter having been shown to perform better in terms of

increasing the drug level that can be incorporated into the pellets. The criteria that ensure an

excipient will function as an aid to extrusion/ spheronization are not known with certainty.

Excipients need to have a binder liquid - usually water - holding capacity, especially when the

wet mass is subjected to pressure. Podczeck et al. indicated that water retention capacity alone

may not be the only factor involved in the performance of spheronization aids.The rheological

properties of the system are also important, but as systems with a wide range of rheological

properties will make satisfactory pellets, this remains to be clearly defined.

CONCLUSION

Extrusion Spheronization is one of them and utilized in formulation of beads and pellets.

Limitations related to bioavailability and site specific drug delivery can be overcome by this

technique. Today extrusion spheronization and melt extrusion spheronization represents an

efficient pathway for novel drug delivery system. The potential of this technology is lies in the

scope for different oral controlled delivery systems including oral and topical delivery systems.

Because of its simple design, high efficiency of producing spheres and fast processing, extrusion

spheronization has found a special position in pharmaceutical industry and especially in case of

production of multiparticulate oral controlled release dosage forms. Pellet formation by this

technique produces more spherical pellets and offers more advantages than other pelletization

process. In addition, hot melt extrusion method has provided a new platform to produce

spherical particles of drugs which are not stable or having compatibility problem in presence of

solvents. There is also scope for developing new methodologies for 715 characterizations of the

pellets.

REFERENCE

1. Chien YW 1982.Novel Drug Delivery Systems: Fundamental, Developmental concepts and

Biomedical Assessments; Marcel Dekker, Inc. New York,pg.no. 139-196,1992.

2. Paolino D, Sinha P . Drug delivery systems. In: Encyclopedia of Medical Devices and

Instrumentation, 2nd ed. John Wiley & Sons, Inc. p.1-4,2006.

3. Chien YW 1989. Rate-control drug delivery systems: controlled release vs. sustained release.

Med. Prog. Technology. 15 (1–2), p. 21–46, 1989

4. Ghebre-Sellassie I et al, Pellets: A General Overview. Ghebre-Sellassie, I. (Eds)

Pharmaceutical Pelletization Technology, Marcel Dekker Inc. New York, 1-13,1989.



5. Deb Ratul et.al,Pellets and pelletization techniques: a critical review,International research

journal of pharmacy, ISSN 2230-8407,2013.

6. Shyamala Bhaskaran,Lakshmi.P.K,et.al, Pellet and pelletization technique, International

Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304,Vol.2, No.4, pp 2429-

2433, Oct-Dec 2010.

7. Lordi NG . Immediate release dosage forms. In: Lachman L, Liberman HA, Kanig JL (eds.) The

Theory and Practice of Industrial Pharmacy. 3rd ed. Varghese Publishing House, Mumbai, p.

430- 451,1992

8. Vishal G. Rathod et.al, Immediate release drug delivery system, world journal of pharmacy

and pharmaceutical sciences, Volume 3, ISSN 2278 – 4357,2014.

9. Nyol Sandeep, Dr. M.M. Gupta,2013, Journal of Drug Delivery & Therapeutics, immediate

drug release dosage forms , 3(2), 155-161,2013

10. Brahmankar DM, Jaiswal SB et al., Biopharmaceutics and pharmacokinetics.Treatise A.

Vallabh prakashan, Delhi. p.335-357,1999.

11. Punia Supriya et al., Pelletization technique : A literature review, International research

journal of pharmacy,ISSN 2230-8407,2013.

12. Mohamed Abbas Ibrahim et.al, Formulation of immediate release pellets containing

famotidine solid dispersions, Saudi Pharmaceutical Journal (2014) 22, 149–156,2013.

13. Gandhi R, Kaul C. Extrusion and spheronization in the development of oral Controlled-release

dosage forms. Research focus. 2(4), 160-170.1999

14. Gibaldi M et al, Biopharmaceutics and clinical pharmacokinetics, 3rd ed.Lea and Febiger,

Philadelphia.p.576-78,1984.

15. Ghebre I et al, Pharmaceutical Pelletization Technology. Vol.37. Marcel Dekker Inc, New

York. p.1-2,1989.

16. Mc Elanay JC et al, In: Encyclopedia of Pharmaceutical Technology, Vol.2, Swarbrick J,

Boylan JC, editors. Marcel Dekker, New York. p.1718,1990.

17. Mike Waldron,et.al, A practical guide to the extrusion and spheronization of pharmaceuticals

using NICA™ System, echPapers/NICA/09.02.2001.

18. Fridrun Podczeck, Dec 1, Preparation of pellets by extrusion/spheronization, Pharmaceutical

Technology Europe, Volume 20, Issue 12,2008

19. Mike Waldron, A practical guide to the extrusion and spheronization of pharmaceuticals

using NICA™ System, Aeromatic-Fielder, TechPapers /NICA/09.02.2001-GB.2009.

20. Vervaet C et al, Remon JP et al,Extrusion-spheronization: A literature review. Ind J Pharm.

116(1), 131-146,1994,

21. Parikh DM, Mehta KA et al, Extrusion/Spheronization as a granulation technique. Marcel

Dekker, New York. 333-362,2009.

22. Schmidt C, Kleinebudde P et al, Influence of the granulation step on pellets prepared by

extrusion/ Spheronization. Chem. Pharm Bull 47(3) 405-412.

pelletisation technique and extrusion … · 2020. 12. 17. · because pellets disperse freely in...

Documents