A Review on Extrusion-Spheronisation

 

Bhavani Boddeda¹*, Pratyusha Bandaru², Y. Srinivasa Rao²

¹Associate Professor, Vignan Institute of Pharmaceutical Technology, Visakhapatnam.

²Vignan Institute of Pharmaceutical Technology, Visakhapatnam, India

 

ABSTRACT:

Pellets, being multiple unit-dosage forms, are widely used as they offer both manufacturing and therapeutic advantages over single-unit solid dosage forms. There are various techniques to manufacture pellets. Extrusion/ Spheronisation or maramuerization is a rapid, flexible and a multi-step process capable of making uniformly sized spherical particles commonly referred to as spheres or pellets of diameter ranging from about 0.5mm to 10mm. It is a best method as it   has an advantage of excellent product flowability, easy scale-up, high yield, narrow particle size distribution, excellent process repeatability. Various techniques used to produce pellets, steps involved, equipments used, effect of process variables involved in extrusion spheronisation process, evaluation parameters and properties requirement of final pellets produced are covered in review. We highlighted the effect of process variables on final quality of pellet.

 

 

 

 

 

INTRODUCTION:

As defined by Ghebre-Sellassie, (1989)¹; pellets are spherical, free-flowing granules with a narrow size distribution, typically varying between 500 and 1500 μm in size for pharmaceutical applications. They are formed as a result of a pelletization process which is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units. There are different techniques applicable for the production of pellets in pharmaceutical industries which are discussed. Extrusion spheronisation process is one of the best techniques to develop pellets. The main objective is to study various steps involved in the process, equipments used, effect of various process variables on the final quality of pellets, and the evaluation of pellets obtained through extrusion spheronisation process.

 

Spheronisation a form of palletization, refers to the formation of spherical particles from wet granulations. Since the particles are round, they have good flow properties when dried. The obtained particles contains the diameter ranging from 0.5mm to 1mm. spheronisation equipment such as marumerizer (luwa corp) and the Granulator (vector). It is vital for ensuring an accurate dosage of the active ingredients within the tablets². It is a multi step process used to make uniformly spherical particles. It is primarily used as a method to produce multiparticles for controlled release applications. The major advantage over the other methods of producing drug-loaded spheres or pellets is the ability to incorporate high levels of active ingredients without producing excessively large particles.

 

Advantages of spheronisation:³

·         Flow of particles will be optimized

·         Improves the handling characteristics

·         Spheronized particles can be mixed easily

·         Improves the friability and hardness of the particles

·         Spheres can easily be coated

·         Particles provide minimum surface area and volume ratio

Limitations of spheronisation:

·         The amount of fluid needed to achieve spheres of uniform size and sphericity is likely to be greater than that for similar tablet granulation. Poor liquid dispersion will produce a poor quality product.

·         Extrusion/spheronisation is versatile process capable of producing spherical granules having very useful properties. Because it is more labour intensive than more common wet massing techniques, its use should be limited to those applications where a sphere is required, when other granulation techniques are unsuitable.

 

Desirable properties of pellets:

Uncoated pellets have:

·         Uniform spherical shape

·         Uniform size

·         Good flow properties

·         Reproducible packing

·         High strength

·         Low friability

·         Low dust

·         Smooth surface

·         Ease of coating and once it is coated:

·         Maintain all above properties

·         Should have desired drug release characteristics

 

Formation of spheronoids (pellets) as in Figure 1.

1.       Extruded part

2.       Breaking

3.       Spheronising

4.       pellets

 

Figure 1:  Formation of spheronoids

 

Various techniques used in production of pellets¹

·         Solution and suspension layering:

This process uses conventional coating pan or Fluidized bed with conventional top spray or Wurster bottom spray to apply drug/binder Solution or suspension to solid cores that can be inert materials or granules of the same drug.

 

·         Dry powder layering:

This involves the use of rotor-granulators/rotor tangential spray fluid-bed to deposit successive layers of dry powder (drug and excipients) on inert Materials with the help of an adhesive solution/binding liquid.

 

·         Direct powder pelletization:

The technique uses high shear mixers and centrifugal Fluid-bed or rotary fluid-bed granulators to apply agglomeration liquid direct to a powder Mixture of a drug and excipients followed by pelletization by means of a rotating disc. A binder can be added as a liquid (wet pelletization) or added as a molten binder before (or) during the process (melt pelletization).

 

·         Extrusion-Spheronisation process:

This is the most employed technique as it offers. The advantage to incorporate high amounts of active pharmaceutical ingredient, without producing an excessively large particle of drug-loaded pellets apart from being more efficient than the other techniques for producing pellets.

 

Steps involved in the extrusion spheronisation process

Extrusion/spheronization is a multiple-step process capable of making uniformly sized spherical particles referred to as pellets and involving the following sequential steps.⁴

·         Dry blending

·         Wet granulation

·         Extrusion

·         Spheronisation

·         Drying

·         Optional screening

 

Dry blending:

Drug and other excipients are mixed by using high shear mixers to achieve homogenous mixture.

 

Wet granulation:

Binder solution is sprayed on to the surface of drug and excipients dry blended previously. Initially drug and excipients substance moistens to form   liquid bridge  which is solidified to form snow ball like structure (agglomerate) as shown in Figure 2.Various types of equipments used in this process are sigma blade mixers, planetary mixer etc,.^5-8 Formation of homogenous wet mass is an important phenomenon involved in this process, but the equipments used may cause rise in temperature due to which some of the granulation liquid may get evaporated leading to formation of unhomogenised wet mass.⁹ The evaporation can be minimized by using cooling jacket around the mixing chambers. There are two major differences in granulation step compared with granulation for compaction:

·         Amount of granulation fluid

·         The importance of achieving a uniform dispersion of liquid

 

Figure 2: Diagrammatic representation of steps involved in the wet granulation

 

Figure 3: Classification of different types of extruders

 

Extrusion:

Extrusion can be defined as the process of forcing a material through an orifice or die under controlled conditions thus forming cylinders or strands called extrudates. Different types of extruders used in the process are classified as shown in Figure 3 & Table 1.

 

Figure 4: a) Axial extruder b) Radial extruder c) Dome extruder

 

Screw type of extruders:

Screw type extruders consist of one or two Archimedes screws feeding the plastic mass to an axial or radial extrusion screen.¹⁰ In the axial type of extruder, the sieve is placed at the end of the screw. In the radial type of extruder, the sieve is placed around the axis of the screw. In the dome type of extruder, the sieve is placed at the end of the screw as in the axial type but the assembly is in dome shape as shown in Figure 4.

 

Gravity type of extruders:

In the gravity type of extruders, the plastic mass is fed into the extruder’s chamber with the help of the gravity where the oscillating or rotating device pushes the plastic mass through the screen.¹¹

·         Sieve extruders

·         Basket extruders

 

Roll extruders:

In roll extruders, the rollers are used in the extruding of the material.

 

a. Roll extruder with two contra rotating wheels:

Roll extruders has two contra rotating wheels. Both the wheels rotate in opposite direction such that extruded material is extruded out between them in the form of cylinder.¹¹ They are two types, one wheel perforated and two wheels perforated shown in Figure 5.

 

Figure 5: a) one wheel perforated  b) Two wheels perforated

 

b. Perforated cylinder rotating:

Second type consists of a perforated cylinder which rotates around one or more rollers discharging material to the outside of the cylinder shown in Figure 6.

 

Figure 6: Perforated cylinder rotated     

 

c) Piston Extruder

The principle of this extruder is based on piston which pushes the wet mass through the screen situated at the end of the barrel. Ram extruder is best example shown in Figure 7.

 

Figure 7: Piston extruder

 

Table 1: Types of Extruders

Equipment	Description	Main Uses
Extruder head	option	Laboratory: small quantity (10g) development use
Extruder 20	Bench top screen extruder	Laboratory experimental / small scale production (30 g 25 kg /hr)
Extruder 35	Production screen extruder	Lab/Production Low cost-high output (2kg /min) of less dense Extrudate
Extruder 40	Production gear extruder	Quality Extrudate Output 40-100 kg/hr
Extruder 100	Production gear extruder	Quality Extrudate Output 100-500 kg/hr

 

Spheronization

The function of fourth step in the process is to round off the rods produced by extrusion into spherical particles. Spheronization is a process whereby spinning plate or Spheronising plate.¹² These extrudates are broken into small cylinders and consequently rounded into spheres (pellets).¹³ According to Rowe,¹⁴ those plastic cylinders are rounded due to frictional process. In the spheronisation process different stages can be distinguished depending on the shape of the particles i.e., from cylinder over a cylinder with round edges, dumb-bells and elliptical to eventually perfect spheres.  Baert and Remon suggested that mechanism twisting of cylinder occurs after the formation of cylinder with round edges, finally breaking of cylinder into two distinct parts as given in Figure 8.¹⁵ Both parts have round and flat side. Due to rotational and frictional forces involved in the spheronisation process the flat edges fold together like a flower forming the cavity observed in certain pellets. Types of spheronisers are represented in Table 2 and Figure 9. Two geometric patterns are generally used

·         a cross hatched pattern with grooves running at right angles to one another, and

·         a radial pattern with grooves running radially from the centre of the disc

 

Figure 8:  According to 1(a -e) Rowe mechanism and  2 (a-e) Baert and Remon

                  

 

Table 2: Types of spheronisers

 

 

Figure 9: Micro spheronizer & Spheronizer 250

 

Drying

Drying is a process where the pellets obtained by extrusion/spheronization are dried. They can be dried by at room temperature,¹⁶ by using fluidized bed drier¹⁷ or by using oven¹⁸ or micro wave oven. A drying stage is required in order to achieve the desired moisture content drying is often the final step in the process. Drying of the pellets can be accomplished in any dryer that can be used for conventional wet granulations, including spray dryers and fluidized bed dryers.¹⁹ If solute migration occurs during the drying of wet spheres, this may result in:

·         Increased initial rate of dissolution

·         Stronger pellets, and

·         Modified surfaces which might reduce the adhesion of any added film coats.

Optional screening:

Screening may necessary in order to achieve the desired narrow size distribution. Normal sieves are used. If all the previous stages are performed efficiently and with careful development of process and formulation conditions, this step may not be necessary.

 

Table 3: Process variables

 

Effect of various process variables on spheronisation process:

Moisture content:

Moisture content of granules should be between upper and lower limits. If moisture content exceeds the upper limit,²⁰ It leads to agglomeration. If it is below the lower limit, it leads to excess of fines in the final product. In general not more than 10% suggestible.

 

Granulation liquid:

In most of the cases, water is used as a granulation liquid.  Alcohol, water – alcohol mixtures^{15, 21&22} are also used as a granulation liquid. Studies indicated that granulation liquid should contain at least 5% of water. Excess of water in granulation liquid causes hardness of pellet.

 

Extruder type:

Various types of extruders are used in the extrusion process differ in the amount of granulation liquid required, length –radius ratio (L/R- ratio),^23,24 shear rate and shear stress ²⁵ are two parameters which show effect on shape, particle size ,and particle size distribution of the final quality of pellet.²⁶

 

Extruder Screen:

Pore size of the extruder screen is selected based on the requirement of particle size. Various extruders differ in length to radius ratio (L/R ratio).An experiment was conducted by taking two Screens with L/R ratio of 1.8 and 4.²⁵ Extrude from Screen with highest L/R ratio is smooth and .denser than screen with lowest L/R ratio. Bulk density of the spheres is influenced by various extruder screens.

 

Extruder Speed:

Extruder speed should be optimum. Excess speed causes surface impairment.²⁶ Messiah and Valles,²⁷ evaluated a series of lubricants as to their ability to reduce surface impairments in order to obtain higher quality pellets. They found that surfactants with a high HLB value were suitable to reduce the surface defects of the extrude. This was correlated with reduced power consumption during extrusion as the friction at the die wall of the extrusion screen was lowered.

 

Extrusion Temperature:

The control of temperature during the extrusion process is an important feature not only when formulation with thermo liable drug is processed but also in view of the importance of the moisture content. A rise in temperature during the extrusion cycle could dramatically alter the moisture content of the granulate due to evaporation of the granulation liquid. This could lead to difference in the quality of the extrude produced at the beginning and end of the batch. To avoid this some of the scientist used temperature probe and some other used a screw extruder with a cooling jacket around the barrel.²⁸ This jacket has a double function as it can be used to heat the mass in order to give products their necessary plasticity.

 

Spheronisation Speed:

In general an optimum speed of 200-400 rpm is suggestible.²⁹ The spheronisation speed affected the particle size of the pellets.³⁰ An increase of yield of the smaller fraction was seen, probably due to a great degree of fragmentation during initial stages of spheronisation process. In contrast a decreasing amount of fines and an increasing amount of large particles with increasing spheronisation speed correlating with increased mean diameter were also observed. The hardness,³¹ Sphericity, porosity, bulk and tapped density, friability, flow rate, surface structure ³² of the pellets were influenced by a change in the spheronisation speed.

 

Spheronisation Time:

In general, 2 to 10 mins is enough for an extrude to get spheronised. A wide variety of effects was witnessed when assessing the importance of this parameter i.e., an increased diameter,³³ a narrower particle size distribution, higher Sphericity, a change in the bulk and tapped densities, change in yield of certain size range  was observed with extended spheronisation time.³⁴

 

Spheronisation Load:

The yield of pellets of a specific range decreased with increased spheronisation speed at a low spheronisation load and increased with extended spheronisation time at higher spheronisation load.³⁵ Particle size distribution,³⁶ particle size,³⁷ bulk and tapped densities,³⁸ hardness,³⁹ increased with an increasing in spheronisation load.

 

Drying Method:

Pellets dried by various type of drier such as microwave oven, ordinary oven, and fluidized bed dryer shown variation in their final quality. The pellets dried with microwaves differed from those dried in the oven as their surface was rougher and those pellets were porous and of lesser hardness.⁴⁰

 

EVALUATION OF PELLETS:

The properties of pellets are listed in Table 4 together with different evaluation methods. ^41,42

 

Table 4: Properties, Requirements and Evaluation methods

Properties	Requirements	Evaluation methods
Particle shape, Sphericity	Like a sphere	Image analysis
Surface texture	Smooth	Image analysis, SEM
Mean particle size	Between 0.5mm and 1.5mm	Sieve or image analysis
Particle size distribution	Narrow	Sieve or image analysis
Porosity	Low	Mercury intrusion
Density	High	Bulk density determination
Mechanical strength of pellets	High	Friability, Crushing strength
Flow properties	Very(Good)	Angle of repose, Flow rate estimation
Drug content	More than 95%	Dependent on the drug

 

ACKNOWLEDGMENT:

Authors are thankful to Mr. K. Mohan for his help during literature review and Prof. J. Vijaya Ratna, AU College of Pharmaceutical Sciences, for her kind cooperation and suggestions for proper output of present review.

 

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