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Aeromatic-Fielder

A practical guide to the extrusion and spheronization of pharmaceuticals using NICA System
by Mike Waldron

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Contents

1.0 INTRODUCTION 2.0 MIXERS


2.1 2.2 2.3 2.4 PLANETARY HIGH SHEAR CONTINUOUS MIXING FOR EXTRUSION

3.0 EXTRUDERS
3.1 3.2 3.3 3.4 THE RAM EXTRUDER THE SCREW EXTRUDER THE GRAVITY FED EXTRUDER THE NICA SYSTEM EXTRUDER

4.0 SPHERONIZERS 5.0 FORMULATION


5.1 MICRO CRYSTALLINE CELLULOSE (MCC) 5.2 BINDERS (as an aid to Extrusion)

6.0 EXTRUSION AND SPHERONIZING USING NICA SYSTEM


6.1 MIXING 6.1.1 Judging the Wet Mass 6.2 EXTRUSION in the NICA E140 6.2.1 Set-Up 6.2.2 Testing the Wet Mass 6.2.3 Reducing Extruder Load 6.2.4 Judging the Quality of Extrusions 6.2.5 Sharkskin or Sawtooth Extrusions 6.2.6 Screen selection 6.2.7 Optimization of Extrusion 6.3 SPHERONIZATION 6.3.1 Principles Affecting Pellet Quality 6.3.2 Operating the Spheronizer 6.3.3 The Mechanism of Pellet Formulation 6.4 OPTIMIZATION 6.4.1 Repeat Processing

7.0 INTEGRATED PRODUCTION PLANTS

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1.0 Introduction

The production of pellets by Extrusion and Spheronization involves three essential processes: - Mixing of the dry powder components with a liquid to form a homogeneous and evenly wetted mass - Extrusion of the wet mass into cylindrical spaghetti like strands and finally - Spheronization which fragments the strands into short cylindrical lengths and roll-forms them into spheres. Equipment for all three processes are available from several manufacturers and, in the case of Mixers and Extruders, in a number of different forms. This guide will first describe and categorise the basic equipment types available and then give practical guidance on the use of Aeromatic-Fielder NICA System.

2.0 Mixers
There are three general types of mixer typically used in pharmaceutical production of pellets: Planetary, High Shear and Continuous. All produce suitable wet mass for feeding extruders and so the choice is non-critical on small or laboratory scale. In a production environment however, the practicality of handling and feeding materials favour the High Shear or the NICA Continuous Mixer.

2.1 Planetary Mixers Planetary Mixers originated in the bakery and food processing Industries and provide for dry mixing and wetting of the charge. The low intensity work input leads to long processes of typically 30 minutes. Discharge is generally effected by tipping or scooping from the bowl which is far from ideal in large scale operations for feeding an extruder.

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2.2 High Shear Mixers With 10 to 15 minutes processing times the High Shear mixers have generally supplanted planetary mixers in pharmaceutical production. Shortened processing times are achieved by higher tool speeds, the generation of shear rather than kneading action in the product and the provision of a chopper for size reduction of agglomerates and to assist in the fast and even distribution of liquid. The high intensity of mixing makes practical the use of liquid spray systems which also assists in speeding up the process. Discharge is typically through a side mounted valve. Using a variable speed impeller linked to level control in the Extruder hopper, enables a High Shear mixer to be directly coupled. However, the need to empty the High Shear before loading the next batch of dry powder requires the Extrusion/ Spheronization process to be temporarily halted.

2.3 Continuous Mixers Continuous mixing of wet mass is not commonly used in Pharmaceutical Production because such equipment tends to be large scale and to have inherent start-up and shut-down losses of material. Consequently, with the relatively small scale production volumes in Pharmaceuticals and the high value of many ingredients, continuous mixing is not seen as economic.

2.3.1 NICA M6 The NICA System Continuous Mixer has been down sized to an output of 2 to 6 kg/minute and at this size is ideally suited to feeding the larger production scale extruders. Moreover, the mixing process is not only continuous but effectively instant and without start-up and shut-down losses; it can therefore be run upon demand to supply the downstream processes. There are no scale-up issues because irrespective of run-time the mixing conditions remain the same. Finally, the production of wet mass upon demand for the Extruder means that there is a minimum of product in process and the delay between mixing and extrusion is constant - a useful characteristic if the mechanical properties of the wet mass change with time. The NICA mixer can be arranged to discharge directly into the extruder hopper giving a compact installation; however, as the mixer cannot perform dry blending of the powders, this has to be carried as a separate operation after the dispensary - usually by tumbling of the bulk container before loading onto the Mixer.

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2.4 Mixing for Extrusion Wet mixers in the Pharmaceutical Industry are most generally used to produce granules for drying and subsequent tablet compression. Tabletting formulations are created specifically for this purpose and generally require a high work input to bind the powders together and build the granules. For extrusion the formulation requirements are different; a robust granule is not required and should not be sought. Extrusion formulations tend to be wetter (20-40% LOD) than those of granulation (10-20% LOD) because of the excipient components used and the need for the wet mass to pass through a screen. Extrusion formulations require even wetting without high work input or massing. The mixing regime should be constructed with these principles in mind.

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3.0 EXTRUDERS
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.

3.1 The Ram Extruder This simplest form of extruder, commonly used for academic study, is made from a piston running in a barrel with a single or multiple holed die at the discharge end. Pressure is produced with a minimum of shear work and certain formulation characteristics are easily studied. A minimum pressure must be generated before extrusion begins, (or can be maintained). Extrusion is continuous at this pressure until the Ram is nearly empty, at which point pressure has to rise because of complex flow patterns set-up as the piston face approaches the die plate. As a production tool, other than for very small quantities, the Ram extruder is of no practical value.

3.2 The Screw Extruder Screw extruders have been used for many years in the plastics, rubber and food industries and have been adopted into pharmaceutical use. Shear work is put into the wet mass as the screw rotates in the barrel. A pressure gradient is set-up along the length of the barrel and when the minimum extrusion pressure is reached at the die end extrusion begins, the process is continuous if the inlet end is kept supplied with wet mass. Twin screw extruders can have kneading and mixing sections fitted at the feed end so that wetting can be carried out in the barrel - however, this facility is rarely used due to the difficulty of optimizing the two processes when they are performed at a common speed. Work input and high temperature rise tends to be high in screw extruders due to the length of barrel and shear work input required to generate the required pressures. This can lead to moisture gradients in the barrel as liquid migrates towards the low pressure end. In extreme cases this can cause seizure after a period of operation if the moisture loss severely effects the rheology of the product in the barrel. To control heat gain the extruder barrel can be water cooled. Throughput can be increased by replacing the normal flat axial screen on the barrel end with domed or cylindrical screens. Finally the discharged extrusions are easily collected for batching into a Spheronizer.
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3.3 The Gravity Fed Extruder In this design the product is gravity fed into two hollow, meshing, gears. The die is formed by drilling holes between the gear teeth through to the hollow bore. As the gears rotate each gear tooth enters the gap between the two opposite teeth producing a form of piston (ram type) action and pressurises the product through the die. It is not possible to produce a true ram extruder effect due to the imperfect fit of the gear teeth which results in leakage both around the flanks and ends of the teeth. Consequently, there is a significant degree of shear work input and throughput is low. The extrusions fall into the bore of each gear wheel and these are set at an incline to assist discharge. The more plastic or sticky materials tend to cause blockages. Finally, to alter the die length or diameter involves changing the gear wheels which are costly components. In a similar design the gears are replaced by cylinders, one of which is hollow and drilled radially to form the dies. Similar comments apply as for the gear extruder.

Different Extruder types


Screw Extruders

Axial

Radial

Gravity fed Extruders

Gear

Cylinder
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3.4 The NICA System Extruder


The design employs two rotors counter rotating within a cylindrical screen. Wet mass is gravity fed onto the feeder which controls the rate of product delivered to the Impeller which in turn forces the product through the screen. The essential characteristic is that shear work is only carried out on a small volume of product directly prior to extrusion. Work input is minimised and the design does not suffer from moisture gradient. Screen area is large in comparison to other similar sized extruders and so throughput correspondingly high. Extrudate quality and that of resultant pellets is generally un-effected by the rate of extrusion. The degree of compression of the extruded product is controlled by the choice of screen. Many simple formulations can be successfully proceeded through screens with a Diameter/Length ratio of 1:1. More difficult formulations give improved results through thicker screens of D/L Ratio of up to 1:1.5. The NICA extruder can be run with a flooded inlet in which case throughput is governed by the extruder speed, or at starvation in which case throughput is governed by the upstream mixing process. This latter case is the preferred option when linking the Extruder to the NICA Continuous Mixer.

Operating principle of the NICA Extruder


Product being fed

Product being pressurised and Extruded

Extrudate

Perforated screen

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4.0 SPHERONIZERS
In general Spheronizer design consists of a wheel with a friction pattern machined on its top surface and spinning on a vertical axis within a parallel sided bowl. Both wheel and bowl are usually constructed in stainless steel, although coatings are sometimes used to reduce the tendency of some products to stick. Wet extrusions are dropped onto the spinning wheel which fragments them and throws them against the bowl wall. The forming pellets are decelerated by friction against the wall and drop down onto the wheel which accelerates them again so that the process continues. This results in a rope of product circulating around the bowl and the constant rolling action between bowl wall, pellets and wheel gradually forms the pellets into spheres. Wheel speed is variable about a typical 10 metres per second peripheral speed. The essential design is common between different manufacturers so it remains only to point out the particular features of the NICA System Spheronizer:a) Smooth Edged Wheel - this patented feature adds a smooth chamfered edge to the friction wheel rim. Circulating pellets, which must make the transition between the moving friction surface and the stationary bowl wall, thus avoid the milling action of being caught by friction pattern against the bowl wall. b) Interchangeable Friction Patterns - the smooth edge rotor can take different friction pattern inserts including Radial and Rectangular Cross Hatch Patterns. c) Close Fitting Wheel/Slit Air - the radial clearance (slit) between wheel and bowl is only 0.15 to 0.3 mm which, together with the smooth edge, results in only small amounts of dust falling beneath the wheel. In this way the provision for slit air need only be used when it is required as an aid to spheronizing (to reduce moisture build up and particle agglomeration) and not to control the loss of product beneath the wheel. d) Controlled Discharge - the product discharge design produces a controlled stream of pellets which facilitates the subsequent pneumatic conveying of pellets into the dryer.

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5.0 FORMULATION
The conflicting requirements of the extrusion and spheronization processes as regards the properties of the wet mass have been discussed in Section 2. Although the principle of operation of the extruder can help minimise the effects of moisture gradients and excessive work input it remains fundamental to the success of the process that the formulation imparts suitable properties to the wet mass. In rare cases the properties of the active compound in conjunction with typical excipients such as Lactose or Dicalcium Phosphate will produce acceptable pellets but this is generally a strong compromise resulting from formulation constraints.

5.1 Micro Crystalline Cellulose (MCC) In the great majority of cases the formation of pellets is greatly facilitated by the presence of 20% or more of Micro Crystalline Cellulose in the dry weight of the formulation. MCC has been widely studied and is the subject of continual development by the FMC Corporation in the USA among others. Two FMC grades are commonly used in extrusion/spheronization, these being Avicel PH101 and PH102. These and other grades are also essential components of pelletization formulations for High Shear and Rotary Processor techniques. This Guide will not attempt to fully explain the action of MCC which is covered by numerous publications. However, the structure if MCC is essentially fibrous and highly porous and is able to absorb large quantities of solvent before becoming fully wetted. When under compression some of this moisture can be liberated and become available to plasticise the wet mass and permit it to flow through the die. On the die exit the pressure is released and the free solvent re-absorbed, returning the extrudate to its earlier stiffer state. Once in the Spheronizer the MCC performs a second time. The extrusions fragment on impact with the wheel but are then repeatedly compressed between the bowl wall and other pellets as they circulate. A further densification of the product takes place and solvent is squeezed out of the structure first providing the required plasticity and then evaporating from the pellet surface to leave a stable entity not prone to further growth. It is the high solvent absorption of MCC in extrusion formulations which leads to their high solvent capacity compared to normal Granulation formulations. (ref: 2.4) The presence of MCC also generates a degree of buffer in the formulation making the process more stable against the normal fluctuations in solvent content. If under wet however MCC will not release sufficient solvent and will result in high extruder loads. The triangular illustrations attached in Figures 1 and 2 show the performance envelope of the NICA E140 Extruder operating on two formulation models. Figure 1 shows a Soluble Active model comprising -Lactose, Avicel PH101 and Water and using 1.0 x 1.0 mm thick screens with
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Punched, Drilled and conical drilled Profile screens (re: 6.2.6). Figure 2 shows an Insoluble Active model with Dicalcium Phosphate, Avicel PH101 and Water. These diagrams represent the proportions of each component in the wet mix. Correcting to dry weight it can be seen that with the appropriate choice of screen the MCC content in the Soluble model can be as low as 10% and in the Insoluble model 30%.

Soluble active model in NICA E140 Nominal screen dimensions 1.0 x 1.0 mm

(fig.1)

B-Lactose

B-Lactose

B-Lactose

Water

Water

Water

Avicel

Avicel

Avicel

Punched Screen

Drilled Screen

Profile Screen
(fig.2.)

Non-soluble active model in NICA E140 Nominal screen dimensions 1.0 x 1.0 mm

Dicalcium Phosphate

Dicalcium Phosphate

Dicalcium Phosphate

Water

Water

Water

Avicel

Avicel

Avicel

Punched Screen

Drilled Screen

Profile Screen

5.2 Binders (as an aid to Extrusion) Although normally used in granulation formulations some binders, in small quantities, have been found useful in assisting the extrusion of difficult formulations. The operating mechanism appears to be as a form of die wall lubricant and a general aid to plasticity of the wet mass. Hydroxy Propyl Methyl Cellulose (HPMC), at a dry weight concentration of 1 to 2% and using lower viscosity grades, has been successfully used in both soluble and insoluble active formulations where the MCC content was lower though ideal. In a particular example, with an almost insoluble active content at 85%, extrusion and spheronization were successful with 14% MCC and 1% HPMC.
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6.0 EXTRUSION AND SPHERONIZING USING NICA SYSTEM


Development of a successful process depends primarily upon a viable formulation and then upon the correct choice of Mixing Extrusion and Spheronization parameters. The essential requirements are: a) Mixing - the product should be evenly wetted but not over-massed b) Extrusion - the extrusion should be cylindrical and should break under its own weight at typically 20 to 50 mm in length. (larger lengths can work) c) Spheronization - the extrusion should fragment into short cylindrical lengths, pro duce a full roping action in the bowl and should form round pellets in 2 to 4 minutes. We can expand upon these requirements as follows: -

6.1 Mixing Planetary mixers can be run at normal granulating speeds. High Shear mixers are frequently best run at low speeds to avoid over massing of the product. Once the product is wetted there is no need for further mixing. The NICA Continuous Mixer is generally run at 2 to 4 kg min. with the standard 2,800 rpm mixing wheel speed and an open discharge orifice. There should be only 2 to 4C product temperature rise and a low, steady, motor load.

6.1.1 Judging the wet mass When wet the average formulation will form an easily compacted solid ball in the hand. When a smaller quantity is squeezed (compressed and sheared) between thumb and forefinger, the product should be found to glide - in effect, it becomes plastic under pressure. This simple demonstration and check shows that the Avicel is sufficiently wetted to perform its main function.

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6.2.Extrusion in NICA E140


6.2.1 Set-Up Fit a Punched screen into the extruder with hole diameter just below the required mean particle size (e.g. a 1.0 mm screen will usually give a mean particle diameter around 1.1 mm). Set the feeder and impeller speeds at 1/3 to 1/2 of the full speed (E140, 60F/50I, E220 45F/40I) and note the no-load currents.

6.2.2 Testing the Wet Mass Bring the wet mass up to a consistency where the glide referred to in 6.1.1 is just evident and feed a small quantity into the extruder (E140 300 gms., E220 600 gms.). Observe the effect upon impeller motor amps which should remain below 90% of full load current. Examine the extrusions produced for cylindricity and length. If they are cylindrical and under 100mm long proceed to section 6.2.5. If they are not cylindrical or are very short, or if the motor current rises to the full load current of the impeller motor it indicates that more wetting is required.

6.2.3 Reducing Extruder Load If the Extruder is producing cylindrical extrusions, 20 to 50mm long, but the Impeller motor load remains non-sustainable it can be reduced in two ways:First - reduce the feeder speed. This reduces the rate of product feed to the Impeller and hence its load. If a drop of 10 rpm on the feeder has negligible effect then:Secondly - lower Impeller and Feeder speed together in 10 rpm steps. This effectively lowers the gearing on a variator driven machine while calling for a lower power input to the two rotors. NICA System E140 Extruder Variation of throughput with feeder speed (typical)
Throughput (kg/min)
Screen 1.0 x 1.0 mm

Impeller Speed 1.1 1.0 0.9 0.8 0.7 0.6 0.5 45 90 Feeder Speed / rpm 135 60 rpm 40 rpm 50 rpm

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6.2.4 Judging the Quality of Extrusions The most important observation to make is to check that the Extruder is producing full cylinders (that is, that the die is filled) which do not hang in long strands and stick together. QUICK CHECK :- Take about 10 grams of extrusions and shake between cupped hands. If the break into short lengths (less than 10 mm) and do not stick together there is every chance that they will spheronize.

6.2.5 Sharkskinning or Sawtooth Extrusions In many cases the surface of an extrusion may be seen to have a regular circumferential ribbing resembling a saw-tooth pattern - also very commonly referred to as Sharkskin. Even when not visible to the naked eye it may be present when viewed under low power magnification. This is a natural die- exit effect and is quite normal. It is common (and wholly unnecessary) for workers in the field to spend considerable time eradicating this effect - usually by using expensive long die-length screens. Not only will this reduce throughput and raise processing temperatures but the dense and smooth extrusion produced is less likely to fragment into short lengths and will be slow to round into spheres. The ribbing effect may be argued to aid fragmentation by introducing weak spots and they are self evidently absent in the final pellet. There is no evidence to suggest that they produce dust provided the mass is sufficiently wet when extruded. Sharkskinning should not be confused with incomplete die-filling (when the extrusion does not form a cylinder of regular cross section). This is undesirable and is unlikely to produce good pellets of tight particle size distribution. This problem is best solved by choice of a different screen or, in extreme cases, by formulation changes.

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6.2.6 Screen Selection


If the Extruder is not over-working and the extrusion remains as incomplete cylinders there is a strong likelihood that a Drilled or Profile Screen will be required. NICA Extruder hole shapes
Punched holes Conventionally drilled holes Profile (conically) drilled holes

>t (Manufacturing limitation)

<t

>t In special cases < t

The correct selection of extrusion screen is fundamental to achieving the required particle size, quality and size distribution and screen selection becomes an iterative process along with wet mass water content and spheronization. However, the essential screen characteristics are known and summarised below together with listings of the standard screen sizes available.

A. Punched Screens
The following screens are standard stock items: 0.6 x 0.5 0.8 x 0.7 1.0 x 1.0 1.2 x 1.2 1.5 x 1.5 All screens are manufactured in AISI 316 stainless steel.

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Specially manufactured screens can be offered with hole sizes greater than 1.5mm - typically 2.0, 2.5 and 3.0mm. We cannot offer non-standard screens with hole sizes smaller than 1.5mm. The defining criteria on punched screens is that the screen thickness can be no greater than the hole diameter, due to the practical difficulties of punching holes. Below 1mm the screen thickness must be less than the hole diameter. This limitation on thickness, together with the fact that punched holes are not perfectly cylindrical, puts a limit on the amount of compression that can be put into the product and the quality of the resulting extrudate. Consequently, best extrusion results are not obtained with punched screens. However, because they are relatively inexpensive to make in series and because sufficiently good results can be obtained with most well-formulated products, they are the first choice where they can be used.

B. Profile Screens
The following screens are standard sizes but are not held in stock. B.1 Profile screens - standard hole density (same as punched screens) in: 0.8 x 0.7 P 1.0 x 1.0 P 1.2 x 1.2 P 1.5 x 1.5 P B.2 Profile screens - high hole density: 0.8 x 0.7 P.HD 1.0 x 1.0 P.HD 1.2 x 1.2 P.HD 1.5 x 1.5 P.HD 'HD' = High Density 'P' = Profile

These screens are manufactured from AISI 316 stainless steel. Profile screens have conical drilled holes arranged such that the hole converges in the direction of flow. This provides a greater degree of compaction over punched screens, and ensures complete die-fill. Typical benefits from using profile screens are a tighter particle size distribution in the final pellets and less sensitivity to variations in moisture content. However, with the standard hole density the through-put will be reduced and the extrusion temperature higher than with the equivalent punched screens. The high density screens, with a greater open area, largely redress the balance, but are more expensive and less robust.

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B.3 Profile Screens - Small Hole Sizes


The following screens are standard sizes but are not stocked: 0.6 x 0.6 P 0.6 x 0.5 P 0.5 x 0.6 P 0.5 x 0.5 P These screens are manufactured from hardened 304 stainless steel. We use 316 stainless steel for the majority of screens because of its generally accepted pharmaceutical compatibility. However, at small holes sizes, its poor mechanical properties make the screens fragile. It is possible to drill (but not punch) holes in hardened 304 stainless steel and these screens have now found pharmaceutical applications where 304 stainless steel has been considered acceptable.

B.4 Special Profile Screens


The above size ranges are designed to match the great majority of user requirements. Screens with non-standard hole diameters and thicknesses can be made with no particular limitation on choice other than the subsequent cost of manufacture. We recommend that before any special screens are contemplated, it should be clearly established that the mechanism of sphere formation follows the classical route, that is, that cylindrical extrusions fragment into short cylinders which then roll into spheres of mean diameter equivalent to or slightly larger than the screen hole size (ref: 6.3.3). If this is not the case, then the results obtained from the specially manufactured screen may be quite unpredictable.

C. Drilled Screens
Conventionally drilled screens (parallel sided holes) have effectively been superseded by Profile screens. Such screens used to be made with thickness greater than diameter (typically 1.5 or 2mm thick for a 1mm hole) in order to give additional compaction and improved die filling. They were expensive and gave poor throughput. However, special screens are manufactured where requested, particularly to match existing screens currently in use.

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6.2.7 Optimization of Extrusion Having produced a cylindrical extrusion at a sustainable Impeller load any other adjustments for optimization must depend upon results in the Spheronizer. Optimization will be an iterative process between Extrusion and Spheronization.

6.3 Spheronization
6.3.1 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.

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6.3.2 Operating the Spheronizer The batch load should be dropped onto a spinning Spheronizer wheel. Use the following basic set-up for the initial trial:-

Model Load/grams Speed/rpm

S320 1000 600

S450 2000 450

S700 6000 300

Once in the bowl observe the roping action and see that all the material is circulating - there should not be a stagnant ring of product on the top of the rope. If the roping action is poor a small amount of product may be discharged with the Spheronizer running or the wheel speed increased 20%. If the problem is not remedied by these means a baffle may be placed against the bowl side to deflect the top of the rope into the centre.

NICA Spheronizer - Optional product deflector

Stagnant Material

Height adjust defector diverts stagnant material into the centre

Circulating Rope

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6.3.3 The Mechanism of Pellet Formation On early spheronization runs take small samples of pellets immediately after loading and at 30 second intervals. Examine them under a magnifying glass and observe the mechanism of pellet formation. The extrusions should fragment into short cylinders which then roll into spheres in under four minutes. If the extrusions fragment into non-cylindrical particles of wide particle size distribution the process will take longer than necessary and may result in a wider than necessary pellet size distribution, there will also be a danger of sticking to the bowl walls. Moisture Content If the extrusion fragments to short cylinders which then grow oversize the mix is too wet. If they fragment into small particles they are too dry. If the extrusions fragment to non-cylindrical pieces which then grow oversize the mix is too wet but will also require a change of extruder screen to improve the extrusions. If the pieces will not form pellets and begin to dust the mix will require more wetting and possibly a change of screen.

Mechanisms for sphere formation Poorly formed Extrusions fragment and build spheres slowly

Well formed Extrusions

break into short lengths

and round quickly

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6.4 Optimization Obtaining the roundest spheres with the narrowest particle size distribution is a question of finding the best balance between 1. Mixer - Moisture content of the Wet Mass - must be wet enough to extrude but not so wet that there is uncontrolled pellet growth in the Spheronizer 2. Extruder Screen Selection - which must provide cylindrical extrusions which fragment to regular short lengths and are not so dense that they will not round in the Spheronizer. There is a clear link between the moisture content of the wet mass and the work input during extrusion which in turn is affected by screen hole diameter and thickness. If the work input is higher, the compaction will be increased. 3. Spheronizer Load/Speed/Time - all three parameters can be used and balanced to give the required work input to achieve roundness (already described in section 6.3.1).

Typical effect on particle size distribution of moving from punched to profile screen (1.0 x 1.0 screen Lactose Avicel placebo)
Weight (%)

80

Punched Screen
60

40

20

0 0 80 500 630 710 800 900 1000 1120 1250 1400 Mesh Size ()

Profile Screen
60

Weight (%)

40

20

0 0 500 630 710 800 900 1000 1120 1250 1400 Mesh Size ()

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6.4.1 Repeat Processing Although much can be learnt from mixing/extruding/spheronizing small individual lots it will eventually become necessary to try a longer extrusion and repeated spheronization. To match the production environment the Extruder needs to be allowed to reach its equilibrium temperature. Likewise, the Spheronizer will take several successive sub-batches to reach its equilibrium conditions of moisture (within the bowl) and machine temperature. In practice there are two significant effects: 1. Pellet Growth The particle size distribution tends to rise slightly (less than a sieve fraction of the mean) during the first two or three sub-batches. 2. Product Build Up There may be a tendency for product to build up on the friction wheel. Both these conditions indicate the need to reduce moisture content by (usually) to 1% in the wet mass. If pellet growth remains a problem (because of increased load in the Extruder due to moisture reduction), then small amounts of purge air can be used (increments of 0.1 bar) to provide a degree of drying in the Spheronizer and consequent stabilization of the pellets. Best results are obtained when Spheronizer parameters are chosen such that variations of one minute of spheronization time about the mean make little difference to mean pellet size. The process is then stable.

NICA System temperature rise in process - Main heat gain is from the extruder - The plant takes time to reach equilibrium (may be preheated) - Pellet size distribution starts small then stabilises after about three cycles - Vapour extraction is necessary to avoid heavy condensation
Spheronizer 2-6C Extruder 2-30C Mixer 2-8C

TechPapers/NICA/09.02.2001-GB

Extrusion and Spheronization of pharmaceuticals using NICA System - Page 23

7.0 Integrated Production Plants


Pelletizing plants can be constructed in a variety of ways to produce the desired output. The table below gives the approximate capacities of the different equipment in the range.

Equipment Capacities Mixer M6


2 - 6 kg/min

E140
0.5 - 2.0 kg/min

Extruders Spheronizers S450


0.4 - 2.0 kg
2 - 6 minute cycle

E200
2.0 - 8.0 kg/min

S320
0.2 - 1.0 kg

S700
2.0 - 10 kg

The heart of any system is the extruder/spheronizer combination. Since the spheronization cycle is usually the rate limiting step in the cycle it is common to link one extruder to two spheronizers through a shuttle box. The following table gives approximate plant capacities.

Combined Units

SCALE
- Pilot - Small - Intermediate

EQUIPMENT
E140/S450 E140/Two x S450 E220/Two x S450 E220/S700 E220/Two x S700

TYPICAL PRODUCTION OF WET PELLETS


30kg/hr 60kg/hr 60kg/hr 90kg/hr } } } }
Sometimes less, often up to twice as much

- Large

180kg/hr }

TechPapers/NICA/09.02.2001-GB

Extrusion and Spheronization of pharmaceuticals using NICA System - Page 24

The Pilot and Small Scale Plants are illustrated blow showing a collector/dumper for the single spheronizer and shuttlebox for the twin spheronizer. NICA System E140 / S450 pilot scale plant

E140 / 2 x S450 small scale plant

Spheronizers moved forward to give access for cleaning maintenance

E140

Shuttle box

S450

S450

TechPapers/NICA/09.02.2001-GB

Extrusion and Spheronization of pharmaceuticals using NICA System - Page 25

Fully integrated plants can be built with the feed of wet mass from either batch or continuous mixers. The use of a continuous mixer brings the significant advantage that plant throughput is set at the output of the mixer with the downstream extrusion running at starvation; this avoids complex discharging cycles from a batch mixer and downtime while it is reloaded and the wetting process repeated. One or more batch driers can be used with each receiving a certain number of spheronizer sub-lots before raising the drying temperature to complete the cycle. Continuous driers may be used as an alternative to batch units.

A complete pelletizing plant is illustrated in the diagram below

TechPapers/NICA/09.02.2001-GB

Extrusion and Spheronization of pharmaceuticals using NICA System - Page 26

Bulk materials are sieved and weighed into a batch sized container which passes to a tumbler for dry mixing. The bulk container is lifted and positioned over a NICA M6 continuous mixer which feeds an extruder/spheronizer combination. Wet pellets are air conveyed into a batch dryer. When dry the pellets are sieved again with the useable fraction passing to a tablet coater.

Feed Feed Bin

Screw Feeder Tank Mixer Extruder


Exhaust air

Pump E220

Fluid Bed Dryer

Collector/Dumper Spheroniser

S700 Steam

Water treatment unit

Product

Potable Water

Air

REV. OS. Water

Integrated Pelletizing Plant NICA M6 Mixer / E220 Extruder / S700 Spheronizer / Size 6 Fluid bed dryer with CIP

TechPapers/NICA/09.02.2001-GB