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Granulation With Rapid Mixer Granulator (RMG) : A ReviewSubmitted by on Fri, 01/04/2008 - 04:02

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Dr. Mukesh Gohel

Dr. Rajesh Parikh

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Dhaval Patel, Bharat Pagi Middle Row-Sitting (Left to right): Vivek Patel, Aniket Ladani, Bhavik Patel Last Row-Sitting (Left to right): Amar Rana, Praful Vahoniya, Kalpen Patel

Krishnakant Sarvaiya and Stavan Nagori

1. INTRODUCTION

1.1 HISTORY

1.2 COMPARISION OF DIFFERENT GRANULATION TECHNIQUES

1.1 HISTORY (1)

1892:

Figure -1 The starting (1)

In 1892, Walloon engineer, Emiel Collette, lost his heart to a girl from Antwerp.This love story led to the foundation of "Werkhuizen Collette" in the center ofAntwerp. "Werkhuizen Collette" was a mechanical construction company thatproduced mainly dough mixer-kneaders for the bakery industry. During the firstdecades of the 20th century the company knew a steady growth and becamewidely known for the robust and reliable execution of their equipment.

1920 TO 1930:

After World War I, Mr. Alfred Collette took over the lead of the company from hisfather and focussed on the growing industrialization. Collette NV was nowproducing machinery for several other industry sectors than the bakery industry.For example, paint mixers, potato scrapers and almond crushers were part of themachine range Collette NV had to offer.

Figure -2 Expansion (1)

1940 TO 1960: INTERNATIONALIZATION

After World War II, Collette NV knew a revival by expanding the scope of theirequipment to the pharmaceutical industry. Besides industrial mixers they now



also manufactured planetary mixers for both food and pharmaceutical industry. Atthe end of the fifties, Alfred Collette's son-in-law, Ir. Emiel Sanctorum, came incharge of the company and he invested a lot in research for new machinery andin export activities, especially to France and the BENELUX. Under his impulse,Collette NV knew a tremendous growth and the company had to move to a moresuitable location then the centre of Antwerp. In 1963, the factory was moved toWommelgem, where it is still located. As for the investment in new technologies,the most important developments from this time were the high speed kneader(SM-series), which would later turn out to be the predecessor of the first machineespecially designed for pharmaceutical industry, and the MICO Collette, anautomatic grinding machine originally designed for in-house use, but now stillused by many large companies in the automotive industry.

1970 TO 1980: THE PHARMACEUTICAL INDUSTRY

The definite breakthrough in the pharmaceutical industry came with theincorporation of Collette NV into the GEI-group in 1972 and with the introductionof the first High Shear Mixer Granulator (GRAL) in 1975. From that time on,Collette NV has become an established name in the pharmaceutical industry.Collette NV stands for innovation, new technologies and service. In 1980 the one-pot concept was introduced with the TOPO-design and the GRAL-processor. In1982, the TOPO-house opened a test lab for the customers, now better knownas the Process development Center (PDC).

1990: CONTINUING INNOVATIONS

Figure -3 Innovations (1)

With the introduction of the Vactron in 1990, Collette NV was one of the firstmachine manufacturers to promote microwave drying for pharmaceuticalapplications, emphasizing its focus towards this industry. But Collette NV alsoremained true to its roots, and still invested a lot in the development of machineryfor the food industry.

In 1993 for example, they introduced the CONVERTICOLL, a continuous mixer-aerator, and in 1998 the CREAM MASTER has been introduced, a continuous fatcream aeration system.

In 1992, when Collette celebrated its 100th anniversary, the original TOPO-househas been expanded, re-planned and re-equipped to become the ProcessDevelopment Center. By now it has become a household word in the industryand many of our customers come there to run tests with their own products.

2000: LOOKING FORWARD TO THE NEW MILLENIUM

Another major event at the beginning of the 21st century was the introduction of

a new range of high shear mixers and single pot processors, the ULTIMATM



range. This new range is the successor of the GRAL and VACTRON ranges andanswers to the strictest cGMP requirements. Its introduction signals thecontinuing focus of Collette on innovation and customer satisfaction.

Today, Collette NV is still located in Wommelgem, near Antwerp, but its premiseshave grown over the years. Under the leadership of Mr. Emiel De Naeghel, theManaging Director of Collette NV until 2002, the company has continued to growand invest in new developments for both food and pharmaceutical industry.

1.2 GRANULATION (4)

The term “granulation” regularly refers to processes whereby aggregates withsizes ranging from about 0.1 to 2.0 mm are produced. The term “pelletization” isused synonymously with granulation, but in pharmacy this term is usually refersto the manufacture of aggregates, preferably spherical, with a narrow size

distribution in the range of about 0.5 to 1.5 mm. (4)

1.2.1 DEFINITION (4)

Granulation is a process of size enlargement whereby small particles aregathered into larger, permanent aggregates in which the original particles can still

be identified.(4)

The major reason for granulating the powdered starting material in themanufacture of tablets and granules are to:

To improve the flow properties so that, the mass uniformity of the dose.To prevent segregation of ingredients in the mixture.To improve the compression characteristics of the mixture.To reduce the environmental hazards for the working personnel due todust formation from toxic materials.To reduce the bulk volume of voluminous powders and make them moreconvenient for storage and transport.

To improve the appearance of the product.(4)

The granules being heavier do not blow out of the die and do not clog the

lower punch.(12)

1.2.2 TYPES OF GRANULATION (5)

GENERAL PROCESS SPECIFIC METHODOLOGY

Wet granulation Wet massing

Fluid bed granulation

Spray drying

Pan granulation

Extrusion and palletizing

Dry granulation Roller compaction

Slugging

Other processes Humidification

Melt pelletization



TABLE 1 PROCESS USED FOR PHARMACEUTICAL GRANULATIONS (5)

1.2.3 GRANULATION MECHANISMS

(A) PARTICLE-BONDING MECHANISMS

During granulation, particles adhere and agglomerate due to bond formation.These bonds should be strong enough to allow granules to withstand handling

without breakdown.(14)(16)

TABLE 2 CLASSIFICATION OF THE BONDING MECHANISMS RELEVANT TO

DRY AND WET GRANULATION PROCESS: - (15)

CLASS MECHANISM

Solid bridges Sintering, heat hardening

Incipient melting due to pressure orfriction.

Deposition during drying

Immobile liquids Viscous binders

Adsorption layers

Mobile liquids Liquid bridges

Capillary forces

Intermolecular and long-range forces Van der waals forces

Electrostatic forces

Mechanical interlocking Shape-related bonding

(B) GRANULE GROWTH MECHANISMS

In the dry methods, particle adhesion takes place because of applied pressure. Acompact or sheet is produced which is larger than the granule size required, and

milling and sieving can attain therefore the required size. (3) The compact masses

are called as slugs, and the process is referred to as “slugging”.(13)

In wet granulation methods, liquid added to dry powders has to be distributed

through the powder by the mechanical agitation created in the granulator(3). Theliquid plays a key role in the granulation process. Liquid bridges developedbetween particles, and the tensile strength of these bonds increases as theamount of liquid added is increased. These surface tension forces and capillarypressure are primarily responsible for initial granule formation and

strength.(13)The particles adhere to each other because of liquid films, and furtheragitation and/or liquid addition causes more particles to adhere. The precisemechanism by which a dry powder is transformed into a bed of granules variesfor each type of granulation equipment, but the mechanism discussed below

serves as a useful broad generalization of the process. (3)

The proposed granulation mechanism can be divided into three stages.



1.Nucleation:

The granulation starts with adhesion among particles due to liquid bridges andthe formation of agglomerates at capillary state. These structures may act as

nucleus for successive enlargement of granules.(17)(18)(19)

2. Transition: (5)

Nuclei can grow in two possible ways: either single particles can be added to thenuclei by pendular bridges, or two or more nuclei may combine. The combinednuclei will be reshaped by the agitation of the bed. This stage is characterized bythe presence of a large number of small granules with a fairly wide sizedistribution. If the size distribution is not excessively large, this point represents asuitable end point for granules used in capsule and tablet manufacture.

3.Ball growth: (5)

Further granule growth produces large, spherical granules and the mean particlesize of the granulating system will increase with time. If agitation is continued,granule coalescence will continue and produce an unusable, overmassed system,although this is dependent upon the amount of liquid added and the properties ofthe material being granulated.

The four possible mechanisms of ball growth are illustrated in Figure.

a) Crushing and layering: (3)

Granules break into fragments that adhere to other granules, forming a layer ofmaterial over the surviving granule.

b) Coalescence: (3)

Two or more granules join to form a larger granule.

c) Abrasion transfer: (3)

Agitation of the granule bed leads to the attrition of material from granules. Thisabraded material adheres to other granules, increasing their size.

d) Layering: (3)

When a second batch of powder mix is added to a bed of granules the powderwill adhere to the granules, forming a layer over the surface and increasing thegranule size. This mechanism is only relevant to the production of layeredgranules using spheronizing equipment.

There is always some degree of overlap between these stages and it is verydifficult to identify a given stage by inspection of the granulating system. For end-product uniformity it is desirable to finish every batch of a formulation at the samestage, and this may be a major problem in pharmaceutical production.

Using the slower processes, such as the planetary mixer, there is usuallysufficient time to stop the process before overmassing occurs. With fastergranulation equipment the duration of granulation can only be used as a controlparameter when the formulation is such that granule growth is slow and takesplace at a fairly uniform rate. In many cases, however, the transition from a non-granulated to an overmassed system is very rapid, and monitoring equipment isnecessary to stop the granulation at a predetermined point, known as granulationend-point control.



Figure 4. Mechanism of Ball growth*

1.2.4 DIFFERENT GRANULATION TECHNIQUES (2)

Granulation is one of the most important unit operations in the production ofpharmaceutical oral dosage forms. However, there are many differenttechnologies each having different strengths and weaknesses. Most companiesprefer which one to use merely based on their own experience.

(A) SINGLE POT

ØProcessing: -

·A mixer/granulator that dries granules in the same equipment without dischargingis commonly called a single pot (Figure 5).

·The granulation is done in a normal high shear processor; however, care mustbe taken to shun the formation of lumps as they cannot be broken down beforedrying.

Figure - 5 A typical single pot set-up (2)

ØVarious options for drying :-



·For small scale: - The conventional heat source comes from the dryer walls,which are heated; the boiling temperature and vacuum are used to reduce andremove vapours. The heat transfer is linked to the surface area of the dryer wallsand the volume of product treated. Therefore, this direct heating method is onlyeffective for small scale use.

·For large scale: - Introducing stripping gas into the pot allows large scaleoperation. A small quantity of gas is introduced in the bottom of the equipment,which passes through the product bed, improving the heat flow from the wall intothe product. The gas also improves the efficiency of vapours removal.

ØLimitation:- As the heated wall is the only source of drying energy, linearscale-up is not possible. This problem is exacerbated if the material to beprocessed is heat sensitive (as this limits the wall temperature); if water is usedas a granulation liquid (it has a high boiling temperature under vacuum and ahigh heat of evaporation); and if used for larger-scale production (thesurface/volume ratio deteriorates as the volume increases).

ØTo overcome these limitations: - Microwave energy can be used. Thisprovides a further source of energy and has the additional advantage, withorganic solvents, that only pure organic vapours must be treated on the exhaustside, and not a mixture of solvent and large volumes of process gas, as would berequired in most other wet granulation technologies.

(B) FLUID BED TOP SPRAY GRANULATION

Figure - 6 Bed top spray granulation (2)

ØProcessing:-

·Granulation can be performed using fluid beds fitted with spray nozzles.

·It is possible to have completely closed material handling by a closed linking withupstream and downstream equipment (Figure 6) Also, fully automatic cleaning(cleaning- place [CIP] and wash-in-place [WIP]) in fluid beds using stainless steelfilters now compares favorably with what is possible in a single pot.

(C) HIGH SHEAR GRANULATION/FLUID BED DRYING COMBINATION



Figure -7 A typical set-up installation at an industrial

scale for the production of pharmaceutical granules (2)

ØThis is the most common pattern used at an industrial scale for the making ofpharmaceutical granules (Figure 7).

ØAdvantages:-

·This system allows full integration with upstream and downstream equipment,and even includes a wet mill between the granulator and dryer.

·With modern control systems it is easy to load, mix and granulate a secondbatch in the high shear granulator whilst drying the previous batch in the fluid bedprior to discharge.

·All equipment can be CIP in a single automatic process. Whereas a singleshaker might be acceptable for drying applications, a twin shaker or blowbackfilter design should be used for granulation processes.

(D) CONTINUOUS FLUID BED GRANULATION

ØProcessing: -

·The equipment is filled with raw material similar to a batch unit.

·After the material has been granulated, the process is switched to the continuousmode allowing material to be introduced via the rotary inlet valve and dischargedas granules by a second outlet valve.

·Monitoring the pressure drop over the product bed can control the process.

·The inlet air is segmented, which allows the product in different areas to betreated with different temperatures. Although the process is effectively plug flow,a significant amount of back mixing occurs during processing.



Figure -8 Continuous fluid bed granulation (2)

(E) FLUIDIZED SPRAY DRYING (FSD)

ØProcessing

·Fluidized spray drying (FSD) produces granules from a liquid in a one-stepprocess Figure 9.

·One option is to produce the active in the primary production as granules, so thatit only requires blending with excipients appropriate for direct compression forsecondary processing.

·This can only be done with actives that are tacky (in a wet state), otherwise theaddition of a binder is necessary.

·Another possible use of FSD technology is to mix all the ingredients into asolution or suspension and to produce granules in a one-step operation.

A principle drawing of an FSD set-up is shown in Figure 9(a). During the FSDprocess, the liquid feed is atomized at the top of the tower in a concurrent mode.After the liquid is evaporated, the particles generated leave the drying chambertogether with the exhaust air. These particles are then separated in a cyclone orfilter and reintroduced into the drying chamber where they come into contact with

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wet droplets and form agglomerates. After these agglomerates have reached acertain weight they cannot leave via the top of the tower with the exhaust air, butfall down into the integrated fluid bed at the bottom of the drying chamber. Herethey are dried and cooled before being discharged.

ØLimitation: - this type of equipment is not easy to clean, particularly theexterior pipework, when changing to another product.

ØTo overcome these limitations: - Systems have, therefore, been developedwhere the exterior pipework does not come into contact with the product (Figure9(b)).

1.2.5 COMPARISON OF GRANULATION PROCESSES (2)

Tables 3-5, a brief overview of the implications of particular granulation methods.

(A) GENERAL ASPECTS $

TABLE – 3 GENERAL ASPECTS (2)

Option1

Singlepot(1)

Option2

HighshearforcemixerandFBD(1)

Option 3

Top spraygranulation(2)

Option 4

Continuoustop sprayprocess (2)

Option 5

Spraydrying (3)

Option 6

Pelleting(4)

SCALESAVAILABLE

LABORATORYSCALE (LS)

TECHNICALSCALE (TS)

PRODUCTIONSCALE(PS)

LS

TS

PS

LS

TS

PS

LS

TS

PS

(TS)

PS

TS

PS

(TS)

PS

DEFINITION OFBATCH

++ ++ ++ Materialcontainer

Materialcontainer

Materialcontainer

SCALABILITY + + + ++(down?) ++(down?)

++(down?)

NEED FORSPECIALBUILDING

Weight Height Height Integrationinto building

Height Integrationintobuilding

ENERGY/kG(5) >0.25kW/kg

>0.25kW/kg

>0.37 kW/kg >0.3 7kW/kg >7.5kW/kg

>0.5kW/kg

YIELD >99.5% >99% >99% >99% >99% >98%



All information shown assumes ‘normal’ products. Some special products may behave differently (1) Granulation with 10% granulation liquid (TS15%)(2) Granulation with 15% granulation liquid (TS15%)(3) Mix all components of formulation in liquid form (TS20%); drying step at the end of primary production canbe saved(4) Granulation with 20% granulation liquid (TS15%)(5) Only drying energy++ very good; + good; +- fair; - poor; -- very poor

ØSCALES

·Option 1 is obtainable in a range of 3–1200 L.

·Option 2 can handle up to 1800 L.

·In fluid beds, batches between 30 g and 2 tonnes can be granulated.

·For the continuous granulation technologies offered as options 4–6, the situationis different. Whereas there exists no upper limit (milk powder granules areproduced by spray drying at a rate of up to 10 tonnes/h), these technologies arenot suitable for very small scale production, even at the laboratory test level, assome processing time is required to achieve equilibrium conditions.

ØBATCH DEFINITION

·This is immaterial to batch technologies offered in Options 1–3, but requiressome discussion for the continuous technologies, mainly if the raw materials arefed in continuously without dispensing and preblending; for example, out of largetanks or silos.

·The most straightforward approach is to accumulate the dry granulates incontainers and define the load of each container as one batch.

·This method is used when operating a tablet press. Often, the size of such acontainer is elected to meet the batch size of a tablet coater.

ØSCALABILITY

·As developments are frequently started in a laboratory, upscaling must beconsidered.

·For Options 1-3, users will only face ‘normal’ up-scaling problems. Often,processes run better when scaled-up.

·Linear up-scaling for the single pot is only possible if microwaves are used,otherwise drying time will be increased.

·For continuous processes, up-scaling is easy because operation time is the onlyparameter to be changed.

·The situation becomes more complicated if it cannot be done by just running thefinal production plant for short periods.

ØBUILDING REQUIREMENTS

·Production scale single pots can weigh up to 10 tonnes. Therefore, a floor ofsuitable strength must be prepared and the logistics of getting the equipment intothe building considered, particularly if the equipment is not to be installed on theground floor.

·For the high shear granulator/fluid bed dryer combination, both a vertical andhorizontal product flow is possible. Because the transfer of wet granules is acritical step, the high shear granulator being in an elevated position makes thiseasier and safer. Therefore, additional height (a platform or separate floor) is

http://www.pharmainfo.net/fluidized-bed-dryer



required.

·Production-scale fluid beds can be some meters high; however, it is notnecessary to install the whole unit in the production room. If it is built as a‘through the wall design,’ all necessary technical installations can be positioned ina technical area.

·The upper part of the fluid bed tower can also be in a technical area above theproduction room. Because of the complex material handling requirements ofcontinuous production (Options 4–6), these systems must be integrated into thebuilding or, better still, the building must be tailored around the installation.

ØENERGY

·As energy consumption for drying is significantly higher than that generated bymotors or vents, only the required drying energy amount is discussed.

·To evaporate 1 kg of water, 0.66 kWh of energy are required.

·The total amount of energy is both a function of the amount of liquid to beevaporated and the grade in which the equipment utilizes the energy supplied.

·The numbers in Table I assume average cases.

Ø YIELD

·The yield of a process is particularly influenced by the time the process takesand formulation. Longer processes increase yield.

·The wetter the granulation process, the greater the material loss (as it sticks tothe walls).

·A third important factor is the total surface area in contact with the product.These factors are not independent from each other. They are also influenced byproduct characteristics. It is, therefore, not possible to provide exact figures;however, the data shown in Table 1 reflect typical scenarios.

(B) FORMULATION ASPECTS

TABLE – 4 FORMULATION ASPECTS (2)

OPTION 1.

SINGLEPOT

OPTION2.

HIGHSHEARFORCEMIXERANDFBD

OPTION 3.

TOPGRANULA-TION

OPTION 4.

CONTINUOUSTOP SPRAYPROCESS

OPTION 5.

SPRAYDRYING

OPTION 6.

PELLETING

CONTAINMENT ++ + ++ + + -

HANDLEORGANICSOLVENTS

++ + + + + +

HEATSENSETIVEMATERIAL

++ + + (+) (+)+(+) (+)

LIMITATION BY none none PSD of raw PSD and flow fine grades limited



DIFFERENTFORMULATIONS

(behaviourmaterial ifexposed tomicrowaves)

materials properties ofraw materials

of rawmaterialsrequired ifworkedfromsuspension

AMOUNTGRANULATIONLIQUIDREQUIRED

8-15% 8-15% 15-30% 15-30% >100% 15-50%

ØCONTAINMENT

·This is necessary if processing toxic or very potent substances. In such case it isimportant to know is it possible to achieve a closed material flow into and out ofthe equipment; if the equipment is tight; and is it possible automatically (includingupstream and downstream connections).

·Closed material flow is possible for all processes shown. Even the very sensitiveprocess of transferring wet granules via a wet mill from a high shear granulatorinto a fluid bed can be done closed. This is achieved by using modern split valvetechnology for contained docking to intermediate bulk containers.

· Although, the first five process options can be supplied in a gastight design, thisis not possible for the pelletizing line (Option 6).

·There are also automatic cleaning problems. Whereas individual machines suchas fluid beds, high shear granulators, single pots or spray dryers can be cleanedusing very efficient automatic cleaning systems (WIP/CIP depending on theproduct), fully automatic cleaning becomes increasingly complicated as moreupstream and downstream equipment are integrated.

·Other important factors affecting containment are how easily exhaust air filterscan be changed without the risk of contamination; whether the equipment isoperated continuously under negative pressure; and to what extent a sample canbe contained.

ØORGANIC SOLVENTS

·If processing with organic solvents, the equipment must be gastight.

·To remove the risk of an explosion it is necessary to either make sure that themixture of organic vapours and oxygen is outside the explosion limits (which cansometimes be achieved in a spray granulation process) or that nitrogen is usedas a process gas. If such processes are to rely entirely on the elimination of allpotential spark sources, they must be carefully checked, case-by-case.

·In addition, passive measures, such as a pressure shock design, suppression orventing, are always required except when using a single pot. This is because therisk of explosion exists only during the drying step, which is done under vacuumconditions. If the exhaust gas contains organic vapours it must be cleaned. Thiscan be done in a closed cycle by cooling, adsorption or catalytic burning. Again,the single pot, particularly if used without stripping gas, has an advantage: onlythe pure organic vapours must be treated.

ØHEAT SENSITIVE MATERIALS

·To treat heat sensitive materials successfully, the temperatures and exposuretime must be carefully controlled, as should the presence of moisture and oxygen.

·Single pot technology provides safe drying under vacuum, particularly if the



granulation is done with organic solvents because the corresponding temperatureis even lower.

·In a spray dryer, however, relatively high temperatures are involved, but only fora very short time.

·A batch fluid bed granulator can operate at higher air inlet temperatures whilespraying and during the beginning of drying, reducing the inlet temperatureafterwards to maintain a low product temperature.

ØFORMULATION LIMITATIONS

·High shear granulators are able to granulate all types of formulations.

·For single pot use, the behaviour of all components exposed to microwaveenergy must be considered. Although this is not critical for most materials, itshould be tested for new materials because of the small risk of an unexpectedthermal runaway — the (microwave) absorption behaviour relies on the moisturecontent or on the actual temperature.

·Fluid beds inherently at as a classifier; that is, the particle size distribution (PSD)of all raw materials should be similar. Processing very fine powders can also beproblematic because these particles tend to stay in the filter area. Sometimes thiscan be solved by introducing the spray liquid.

·If a suspension is used to feed the spray dryer the suspended particles need tobe smaller than 30 μm to allow a proper atomization.

·Tailor made formulations containing, for example, a high amount ofmicrocrystalline cellulose are needed to run an extrusion process. Forinadequately soluble actives in particular, the maximum drug load that can beachieved is limited. From a processing point of view, very soluble drugs can alsocause many problems.

ØGRANULATION LIQUID

·For the production of oral dosage forms, high shear granulators have almostreplaced medium and low shear versions because their increased mechanicalenergy requires less granulation liquid to produce granules of similar properties.

·Smaller amounts of liquid added during granulation requires less evaporationduring drying, resulting in a higher throughput and lower thermal stress for theactive.

·The numbers provided in Table I largely depend on the nature of the formulation;whether the binder is added in a liquid or a solid form; and the granulecharacteristic required

(C) COMPARISON OF GRANULE CHARACTERISTICS OBTAINED BYDIFFERENT MAETHOD

TABLE – 5 CHARACTERISTICS OF GRANULES (2)

OPTION1.

SINGLEPOT

OPTION2.

HIGHSHEARFORCEMIXERANDFBD

OPTION 3.

TOPGRANULA-TION

OPTION 4.

CONTINUOUSTOP SPRAYPROCESS

OPTION5.

SPRAYDRYING

OPTION 6.

PELLETING

DUST/ FINE <12% <8% <5% <3% <1% none



PARTICLES

D50;PSD 100-800m

120-800m

150-600 m 120-400 m 150-300m

800-2000 m

SPAN (6) 2.5-3 2.5 2 2.5 1.5 <1

HOMOGENEITY+ + + (+) ++ +

FLOWPROPERTIES

+ +(+) + + + ++

BULK DENSITY0.7g/cm3 0.8g/cm3 0.7g/cm3 0.7g/cm3 0.6g/cm3 nearphysicaldensity

DISOOLUTION + + ++ ++ ++ -

(6) Span =(D90_D10)/D50

ØAMOUNT OF FINE PARTICLE

·If the percentage of fine particles (63 μm) is too large, flow problems,segregation and poor tablet formation become common issues.

·The numbers shown in Table III are a reflection of the formulation and processparameters. If Option 6 is taken, no fine particles in the final product occur as allmaterial is incorporated into the extrudate. For Options 4 and 5, fine particlescannot be discharged (because of the way in which the equipment operates), butare blown back into the operation zone where they are likely to be bound intogranules.

·The relatively high amount of fines for the single pot process is typical of alltypes of vacuum drying. If seen as problematic, but adjusting the formulation canreduce this.

ØMEAN PARTICLE SIZE

·All processes allow the mean particle size to be controlled by varying someprocess parameters. The given limits can, in some cases, be extended forbespoke equipment.

ØSPAN

·The span describes how narrow a PSD is. All results shown are not critical fortablet compression, but may be of some interest if the granules are sold as a finalproduct.

ØHOMOGENITY

·All technologies presented generally show no problems with producthomogeneity.

·Mixing all components in a liquid stage followed by granule production in a one-step operation will give the best homogeneity level.

·The material produced in the continuous fluid bed granulator might, in rarecases, show some homogeneity problems, mainly if the material produced justafter start-up and just before close down is examined separately and is notblended with the material produced in between.

ØFLOW PROPERTIES

·Achieving free flowing materials is a major reason for including granulation.Therefore, only processes able to fulfill this requirement are of interest.



·The slight differences shown in Table III result from the fact that high sheargranulation in general produces more dense and mechanically more stablegranules.

·During vacuum drying, some of these granules are destroyed and a largeramount of fines is generated.

ØBULK DENSITY

·The bulk density required depends on the physical densities of the materialsused, from the amount and type of binder liquid, the process parameters selectedand the process by which the granulation is done.

·The numbers shown in Table III may, therefore, vary for different materials orprocess conditions, but a clear pattern is shown illustrating which process willdrive the bulk density in a particular direction.

ØDISSOLUTION

·How easily granules dissolve (instant properties) depends on their surfaceenergy and structure.

·Granules produced with lower shear forces, such as in Options 3–5, show amore open porous structure, therefore, they show fast dissolution profile,however they are mechanically less stable.

2. RAPID MIXER GRANULATOR (RMG) (6)

2.1 DEFINITION

2.2 VARIABLES

2.3 GENERAL PRODUCTION DESIGN OF RMG

2.4 WORKING PRINCIPLE OF RMG

2.5 INDIAN MANUFACTURED MACHINES

2.6 GLOBALLY AVAILABLE MACHINES

2.7 ADVANTAGES AND DISADVANTAGES

2.1 DEFINITION (21)

High shear mixer Granulator guaranties a homogeneous and foreseeable endproduct.

Because with it you obtain:

Compressibility and fluidity properties in powdersMechanical properties to pillsBio-disponibilityMixture homogeneity in low actives dosesDoses homogeneity in final product

2.2 VARIABLES

2.2.1 PROCESS VARIABLES

Process variables that affect granulation process are as follow:

ØImpeller rotation speed

http://www.pharmainfo.net/tablet-evaluation-tests/dissolution

http://www.pharmainfo.net/tablet-evaluation-tests/dissolution



ØChopper rotation speed

ØLiquid flow rate

ØLoad of the mixer

ØLiquid addition method

ØWet-massing time (subsequent of liquid addition time)

2.2.2 PRODUCT VARIABLES

Product variables that affect granulation process are as follow:

ØAmount of liquid binder

ØCharacteristics of liquid binder

·Surface tension

·Viscosity

·Adhesiveness

ØCharacteristics of the feed materials

·Particle size and size distribution

·Particle specific surface area

·Solubility in the liquid binder

·Wettability

·Packing properties

2.2.3 APPARATUS VARIABLES

The instrumental variables affecting the granulation characteristics are:

·Size and shape of mixing chamber

·Size and shape of impeller

·Size and shape of chopper

2.3 GENERAL PRODUCTION DESIGN OF RMG (20)

The High Shear Mixer/Granulator is a multi-purpose processor equally suitable forhigh speed dispersion of dry powders, aqueous or solvent granulations, and

effervescent products and melt pelletization.(11)

There should be both simplicity and flexibility in plant design. User-selectedprocess options, cleaning equipment, control systems and PAT technologiescombine in a system to meet process requirements exactly. This approach

ensures that qualification and validation procedures are kept to a minimum. (20)

2.3.1 THROUGH-THE-WALL CONFIGURATION (20)

Through-the-wall offers the best option in terms of cleanliness, maintenance andATEX. By keeping the motors out of the process room, you are preventing risk ofcontamination coming from these difficult to clean items. Maintenance is carriedout from the technical area, minimizing the need for the maintenance engineer towork in a GMP area. This makes the job easier and again reduces the risk ofcontamination.



For ATEX, the design allows us to classify the technical area as safe. This avoidsthe need for costly flameproof motors, making the upgrade The frame mountingprovides a standard format for the machine, allowing it to be constructed andinstalled using the same structure. This structure may be raised using standardmodules to achieve the customer’s desired height. For some installations it is alsopossible to mount control panels on the structure, allowing qualification of thecomplete system prior to shipping, significantly reducing the installation time onsite.

2.3.2 IMPELLER & CHOPPER OPTIONS (20)

(A) STANDARD PMA IMPELLER

Standard impeller designed for use with the conical bowl of the PMA high sheargranulator.

(B)U-SHAPED CHOPPER

Standard chopper for use with the conical bowl of the PMA high shear granulator.

(C) M8 IMPELLER

Innovative swept-back design; for improved mixing characteristics,fasterprocessing and a more clearly defined end-point.

(D) MULTI-BLADED CHOPPER

Flush mounted, multi-blade design improves binder solution dispersion andproduct movement at slow speeds.

2.3.3 FILTRATION (20)

(A) MATERIAL FILTER & SHROUD

Production filtration is achieved using an easily removable material filter that canbe cleaned and re-used. For vacuum and CIP applications stainless steel may beutilized.

2.3.4 DISCHARGING

(A) THROUGH-THE-WALL MILL

Product can be discharged from the high shear granulator directly into a receivingcontainer, or via a sizing mill. This breaks down the granules to produce moreeven sizing for subsequent processing. through-the-wall hinge-mounted sizingmill, directly connected to the discharge port, using inflatable seals. Formaintenance, cleaning and product changeovers, the seals are deflated and the



mill hinged away from the port, allowing full access. The TTW mounting ensuresthe motor and controls are kept away from the clean process area. PressureShock Resistant options are available, matching the containment and safetycredentials of the main machine.

(B) CONCEALED HINGE MECHANISM

The cover is mounted on a concealed hinge mechanism allowing the cover tobelifted with the minimum effort, but keeping the counterweight in the technicalarea. This leads to a more GMP design, reducing surfaces, making cleaningeasier. On equipment supplied with the Pressure Shock Resistant design optionthe hinge interlocking system is power assisted to provide safe and comfortableopening to the bowl cover.

2.3.5 LOADING (20)

(A) GRAVITY LOADING

Simple open / close ports may be mounted on the cover and used to dispenseproduct into the mixing bowl. For potent powders, split-valve technology providesfull containment during loading. The PMA-Advanced™ can also be delivered witha cone loading port, allowing for the removal of the powder loading ports from thecover, but giving permanent connection to a Gravity Loading Station, but alsocontinuous access to open the cover.

(B) VACUUM LOADING

Rapid loading can be achieved using vacuum technology. Aeromatic- Fielder’sinnovative killed-vacuum technique makes for easy operation and maintenance,and only requires a standard-sized filter.

2.3.6 BINDER SOLUTION ADDITION (20)

(A) NOZZLE

A range of nozzles are available to give the optimum binder liquid droplet size foran even distribution throughout the powder mass.

(B) PUMP

The binding solution required for granulation may be pumped into the mixing bowlusing a mechanical or peristaltic pump to deliver the binder liquid to the spraynozzle. Special pumps are available for the dosing of high viscosity binders.

(C) PRESSURE POT

Alternatively a pressure pot offers fast, high-pressure delivery of the binder



solution, for excellent dispersion of liquid via the binder nozzle spray system.These systems are chosen typically for small scale, R&D-sized granulators.

2.3.7 STANDARD PLATFORM DESIGNS (OPTIONAL) (20)

Two standard platforms are available to integrate with the PMA-Advanced™. The"Medium" platform provides room adjacent to the bowl for the operator to carryout all filling and cleaning operations. The “XL” platform additionally providesspace for other items / operators on the platform and also provides sufficientspace to allow the operator interface to be mounted at the platform level. Due tothe clean lines of this design the bowl/ cover area can be easily accessed usingmobile steps. Additionally we can offer bespoke platform design and constructionservices to provide the optimum integration within the available plant area.

Figure 10 Standard platform designs (20)

2.4 WORKING PRINCIPLE OF RMG (5)

The mixers originally designed for mixing of thermoplastics and have later beenadopted and redesigned to meet the good manufacturing practice (GMP)requirements in the pharmaceutical industry. The high shear mixers have beenfurther developed as one pot unit, including the drying process, by use of vacuumassist and microwave or air- stripping systems. The high shear mixers have beenapplied to wet granulation, melt granulation and pelletization, and are set up withprocess control systems.

Pelletization, i.e., the preparation of granulations with a controlled granule sizeand shape, has gained great interest since the 1970s because of its potential forcontrolled-release preparations for peroral administration. Wet processes likeextrusion and spheronization and powder or suspension layering are most

commonly used.(4)

Blending and wet massing is accomplished by high mechanical agitation by animpeller and chopper. Figure shows a vertical high mixer, which is the mostwidely used version in the pharmaceutical industry. Mixing, densification, andagglomeration of wetted materials are achieved through shearing and compactionforces exerted by the impeller. The impeller rotates on the vertical shaft at arotational speed corresponding to a radial blade tip speed of approximately 5-15m/s. the chopper rotates at a similar tip speed which, because of its smalldiameter, corresponds to a very high rotation speed in revolutions per minute(rpm)(i.e. 1500-4000 rpm). The primary function of chopper is to cuts lumps intosmaller fragments and aids the bowl or sprayed onto the powder to achieve amore homogeneous liquid distribution.

The granulation is conventionally performed in the following process steps:



1. Mixing of dry material at high impeller and chopper speeds for a fewminutes (approx. 2-5 min).

2. Addition of liquid binder by pouring it onto the powder, while both theimpeller and chopper are running at a low speed (approx.1-2min.)

3. Wet massing with both agitators running at high speed (approx.1-5min.)4. Wet sieving the granules.5. Drying the granulate.6. Dry sieving the granulate

2.5 INDIAN MANUFACTURED MACHINES

2.5.1 RAPID MIXER GRANULATOR (CHITRA) (7)

Figure 11 Rapid Mixer Granulator (CHITRA) (7)

ØRapid Mixer Granulator is designed to achieve excellent mixing and consistentgranules at lower operating cost along with higher productivity.

Ø Better mixing and closed control of granule size leads to faster tabletingspeeds with improved quality and least rejections.

ØSalient Features :

·Homogeneous binder distribution.

·Short batch time and reduce cleaning time.

·Maximize CIP effectiveness.

·Air purge sealing system for main stirrer shaft and granulator shaft.

·All internal contact parts are polished to the mirror finish.

·PLC based operating panel for precise control of process & automation.

·A high-speed granulator is inserted horizontally through wall of bowl to assistblending of powder and to break the product to the granules of required size.

·The seal housing and drive shaft may be flushed with cleaning water, which isthen drained away from the machine through built in drain tubes.

·Granulator motors is provided with a removable stainless steel shroud whichcovers the motor and simplify cleaning.

·All moving parts of the machine are totally enclosed to eliminate accident.



·The machine cannot be started unless and until the mixer cover is properlyclosed.

·All contact parts are made out of SS304. SS316 provided on demand on extracost.

·Flush wall type discharge valve eliminates pockets at the port of discharge valve.

2.5.2 RAPID MIXER GRANULATOR (SAMS)(8)

Figure 12 Rapid Mixer Granulator (SAMS) (8)

ØThe Sams Rapid Mixer Granulator was developed in close co-operation withpharmaceutical and chemical industry. With the help of RMG wet sifting isgenerally no longer necessary. After the mixing of the dry components,subsequent wet granulation occurs (without transfer of dry mixture) producingloose granules in RMG. RMG is specially designed to meet the GMPrequirements of the pharmaceutical industry.

ØWORKING PRINCIPLE

The Sams RMG working principle is based on 2 decisive factors essential for themixing systems.

1. Spinning close to the bottom of the mixing bowl.

2. The impeller sets the entire mixture in a whirling-rising tumbling motionensuring a quick and even distribution of all dry components, which leads to aneven wetting of every granule. The large lumps occurred during wet mixing arebroken up, by the strategically located chopping tool rotating at 1440/2880 RPM.The mix can be discharged with the impeller running through the outlet locatedon the side of the mixing bowl flush to the bottom. Easy accessibility for cleaningis guaranteed by the low profile. The mixing tool is easily removed from the driveshaft providing an unobstructed mixing area which may be cleaned very easily.

Ø CONTROL PANEL



Figure 13Control panel(8)

·Control Panel is made up of S. S. sheet metal.

·It is with special feature DISPLAY SYSTEM and MICROPROCESSOR withmember keys.

·Display system consists of indicator lamps for compressed air supply, mainmotor, chopper motor, bowl lid limit switch and for closed / open status ofdischarge valve.

·In case of insufficient compressed air supply pressure switch contained in thepanel will prevent the machine from starting.

·Limit switch is provided on main bowl lid, and discharge valve, which will de-energise the system when the lid is open

ØMIXING BOWL

Figure 14 Mixing Bowl(8)

·Dome shaped processing bowl which directs loose particles into whirling motionwith the help of impeller.

·Impeller consists of 2 full and 2 half solid mixing blades.

·Inclination of the mixing blades accelerates rising and tumbling motion of theproduct in the bowl.

·Specially designed chopper blades driven at high speed gives fast and evengranulation, throughout the whole mass in the product bowl.

·For easy accessibility in cleaning the side discharge assembly is provided withhinges.

ØSPECIAL FEATURES

·Unit is designed to meet requirements of GMP.

·Contact Parts can be SS 304 / 316 quality.



·Specially designed control panel with display system and microprocessor.

·Bowl, lid mixing agitator, discharge housing and all other contact parts will bestainless steel.

·All M.S. parts of the machine are cladded / covered with stainless steel

·Components of the machine are having easy accessibility for cleaning.

·All electrical & pneumatic parts are pre-wired to simplify installation.

·Limit switch is provided on main lid and discharge valve for safe operation.

·Discharge can be provided on either side to suit client requirement.

2.6 GLOBALLY AVAILABLE MACHINES (7)

Sr.No.

MFR Size

(liter)

Description

1. COLLETTE 400 ONE (1) Used Collette High ShearGranulating Mixer, Model Gral 400, 400liter capactiy, stainless steel construction,with 960 MM diameter X 600 MM deepbowl with pneumatically operated plugvalve discharge, with bowl lifter and cart, 3speed main blade, 2 speed chopper blade,15/22 KW motor, Serial No. 92GR10400-147, New 1992.

2. DIOSNA 25 ONE (1) Used Diosna high sheargranulating mixer, model P25,25 litercapacity, stainless steel construction,jacketed bowl rated 3 bar (43.5 PSI), 2/2.4KW high speed chopper, 2/2.4 KW maindrive, 460 volt, manually operated plugvalve discharge, WIP design, mounted onstainless steel enclosure with controls,serial no. 241-081.

3. FUJI 10 ONE (1) Used Fuji Powrex High ShearGranulating Mixer, Model FM-VG-10, 10liter capacity, sanitary polished stainlesssteel construction, manually operated plugvalve discharge, 2.2 KW variable speedmain drive, .75 KW two speed chopperdrive, on portable base with controls, SerialNo. 903235, New 1990.

4. FUKAE 2 ONE (1) Used Fukae Powtec High ShearGranulating Mixer, Model LFS-GS-2J, 2liter capacity, sanitary stainless steelconstruction, jacketed bowl, hinged coverwith filter, side chopper, variable speedmain and chopper drives with controlpanel, Serial No. 662, New 1993.

5. GLATT 50 ONE (1) Used Glatt High ShearGranulating Mixer, Model VG50,50 liter



capacity, stainless steel construction,jacketed bowl, with 1.5 KW 3000 RPM highspeed side mounted chopper, 5.5 KW 25-550 RPM main drive, mounted on stainlesssteel enclosure with PLC controller, serialno. 00761, new 1996.

6. GLATT POWREX 25 ONE (1) Used Powrex High ShearGranulating Mixer, model FM-VG-25, 25liter capacity, sanitary polished stainlesssteel construction, jacketed bowl, manuallyoperated plug valve discharge, 3.7 KWvariable speed main drive, 1.5 KW variablespeed chopper drive, on portable base withcontrols, serial no. 933306, new 1994.

7. KEYINTERNATIONAL

15 ONE (1) Used 15 liter Key InternationalHigh Shear Granulating Mixer/Dryer, ModelKG15, 316 stainless steel productscontacts, chamber rated for rull vacuuminternal, jacketed bowl rated to 105degrees C, 3 H.P. DC main motor with 0-550 RPM shaft speed, top mounted .5 H.P.DC chopper motor, mounted on portablebase with Mokon Hot Oil Unit, SiemansVacuum Pump and 6 Line Alpha NumericPLC Controls. Unit New in 1993 and in likenew condition.

8. N/A 60 ONE (1) Used Diosna high sheargranulating mixer, model P-Vac 10/60,stainless steel construction, with 60 literand 20 liter interchangeable bowls, highspeed chopper and main drive, mounted onstainless steel enclosure with controls,serial no. 370-004, new 2000.

9. NIRO FIELDER 25 ONE (1) Used Niro Fielder High ShearGranulating Mixer, model PMA25, 25 Lcapacity, stainless steel construction,jacketed bowl, 1.3/1.8 KW high speedchopper, 5.5 KW DC maindrive, 440 volt,pneumatically operated plug valvedischarge, mounted on stainless steelenclosure, with controls, serial no. 8012,new 1990.

10. T.K. FIELDER 50 ONE (1) Used T.K. Fielder High ShearGranulating Mixer, Model PMA5026, 50liter capacity, sanitary stainless steelconstruction, pneumatically operated plugvalve, with integrally mounted controlpanel, 10/7.5 H.P. 220 volt main drive,2.27/1.54 H.P. 220 volt chopper drive,Serial #2324.



65 ONE (1) Used TK Fielder High Shear Mixer/ Granulator / Dryer, Model SP65, stainlesssteel construction, 65 liter bowl, 7.5 KWmain drive, 0-400 RPM main impellerspeed, 1.3-1.8 KW high speed chopper,1.5 KW microwave heating source, SerialNo. 7829.

300 ONE (1) Used T.K. Fielder High ShearGranulating Mixer, Model PMA3002G, 300liter capacity, sanitary stainlesssteelconstruction, pneumatically operatedflush plug valve, 10/7.5 side entry chopper,operator panel, control cabinet, 440 voltDC main drive with SCR Controller, 220volt controls, Serial No. 2249, Built Feb.1982, mounted on stainless steel base.

400 ONE (1) Used T.K. Fielder High ShearGranulating Mixer, Model PMA-400, 400liter capacity, sanitary stainless steelconstruction, jacketed bowl rated 2 bar (29PSI), 10/7.5 H.P. 1800-3600 RPM chopper,25/30 H.P. 0-200 RPM main drive,on basewith variable speed controllers, withplatform, dustcollector, blower, rotary airlock and associated parts and controls,Serial No. 8268, new 1994.

1200 ONE (1) Complete 1200 liter TKFielder/Niro Pharma SystemsMixer/Granulator/Dryer Installationincluding: ONE (1) Model SP1200 Mixer,with microwave heat source, bowl jacketedfor 70 PSI, 0-140 RPM rotor speed,chopper blade assembly. System includesVac-U-Max Dust Collector, KEU S/SMill,200 gallon Lee Tank with agitator, 40gallon Lee Tank with agitator, S/S PlateExchanger, Toledo Platform Scale, Bal-TrolPneumatic Hoist, Acme Package Chiller,Model DDCA-95, Niagara Series HPCustom Air Handling Unit. System iscomplete with all inter-connected piping,controlsSerial No. 7865, New 1989.

11. ZANCHETTA 400 ONE (1) Unused Zanchetta Roto PProcessor, Mixer/Granulator/Dryer, Model400P, 400 liters total capacity, sanitarystainless steel construction, plug styledischarge valve pneumatically operated,hinged cover, telescopic chopper, tiltingbowl, hydraulic drive, jacketed bowl andcover.



2000 ONE (1) Used Zanchetta Roto GranulatingMixer, Model Roto 2000G, 2000 litercapacity, all sanitary stainless steelconstruction, variable speed hydraulicdrivetelescopic high speed adjustablechopper, standard paddle style granulatingmixer blade, stainless steel base, coverand control console, vacuum rated,jacketed bowl, complete system New in1992, 1859 total hours of service.

2.7 ADVANTAGES AND DISADVANTAGES OF RAPID MIXING GRANULATOR(4)

2.7.1 ADVANTAGES:-

Gravity loadedUnit formula maintainedForms desired wet granule rapidlyLess wetting and more rapid dryingHomogeneously dry mixes quickly: color distribution is excellent; caneliminate premixes of addition by geometric progressionSelf-dischargingImproved coefficient of weight variationImproved content uniformitySanitary constructionRelatively easy to cleanMixing bowl may be jacketedOption to dry granulation with mixerAdequate safety devicesConforms to good manufacturing practices(GMP)

2.7.2 DISADVANTAGES:-

Relatively high costHigh noise levelAdding material directly is not convenientTemperature rise from head of frictionNon movableMust be raised to working heightForeign spare part

3 INNOVATIONS

3.1 UltimaGral™(9)

The basic UltimaGral™ design, first introduced in 1972, is a high shear mixergranulator, in which the processes of dry mixing, wet mixing, and granulation canbe executed. The most important features of this basic design are the top-drivenmixer and chopper, the removable bowl, and the "through-the-wall" installation ofthe larger machines.



Figure 15Ultima™ 25(9)

The basic UltimaGral™ design ranges from 10 L to 1200 L machines.The rangeof UltimaGral™ processors extends the concept of the basic UltimaGral™ andallows us to execute the whole cycle of mixing, granulating and drying in a totallycontained environment.

The UltimaGral™ processors are equipped with a vacuum system to allow dryingof the granulate. The Transflo™ system (gas-assisted vacuum drying) can alsobe provided on UltimaGral™ processors.

Same design of process bowl, mixer and chopper make sure that process andvalidation wise there is no difference to the Collette Gral. This unique design ofprocess bowl, mixer and chopper makes the UltimaGral™ not only a perfect wetgranulator but also an ideal machine for melt granulation and pelletizing.

ØSTAND ALONE ULTIMAGRAL™

Any applications of a high-shear mixer-granulator do not require integration withother equipment. The UltimaGral™ design allows for different ways of setting upa stand-alone machine in a GMP-compliant way:

·The through-the-wall execution: Space saving, GMP compliant.

·In the freestanding execution, all mechanical parts are completely covered andsealed, so the machine remains GMP compliant.

Ø CLEAN IN PLACE (CIP)

Contained processing also requires that the equipment can be cleaned in acontained fashion. The UltimaGral™ can be equipped with a full CIP system thatensures cleaning-in-place of product feed, product filter, bowl and lid anddischarge valve.Downstream equipment such as a mill can be incorporated in theCIP system.

Ø PROCESS TECHNOLOGIES

Apart from executing standard wet granulation processes, the UltimaGral™ canbe used for many other applications, such as:

·Melt granulation

·Pelletization

The UltimaGral™ can produce a wide variety of products which are as follows:-

·Effervescents formulation



·Formulations developed for alternative technologies

·Low binder formulations

·Moisture, heat or light sensitive products

·Vitamins

·Highly potent or toxic drugs

Ø CONTROL SYSTEMS

·Basic solution: OP/PLC based (standard)

·Operator panel as user-friendly interface with the machine

·Paperless recorder for historical trending

·High end version: PC/PLC based, batch oriented software with processvisualization.

·Software compliant with ISA S88.01 and NAMUR batch processing standards,quasi-3D process visualization, and unlimited number of recipes.

·Software designed to be compliant with FDA 21 CFR Part 11.

·Real-time storage of batch information in a relational database.

·Possible integration into higher level business and enterprise planning systemssuch as SAP, etc.

·Video camera for easy visual process monitoring.

The basic UltimaGral™ design is a high-shear mixer-granulator without dryingcapacities. The features of a basic UltimaGral™ high-shear mixer-granulator arethe following:

Ø STANDARD FEATURES

·Top driven mixer and chopper.

·Vertical chopper shaft.

·No seals in direct contact with the product.

·Free standing machine OR through-the-wall design (only for 75 L or larger).

·Easy to wash-in-place (WIP).

·Built to GMP-standards.

·Easy validation.

·Full stainless steel construction in process room.

·Total containment of the product.

·Twin speed chopper and mixer.

·Full interlocked guarding.

·Operator control panel on the machine.

·Easy access for maintenance.

3.2 VG SERIES (10)

A Glatt VG (Vertical Granulator) allows extremely fast Wet granulation with highgranulate densities and thus very good particle stability. Batch sizes varies from

http://www.fda.gov/



100l to 3000l/batch.

Figure 16 Vertical Granulator(10)

Ø IDEAL PROCESS PARTNER

A vertical granulator is the perfect partner for a fluid bed dryer for optimumeconomy. Pellets can be manufactured if the vertical granulator is combined witha spheronizer/pelletizer for subsequent spheronization of the granulate. Single-Pot systems provide the facility to dry the granulate. For the use of organicsolvents, the vertical granulator can be combined with a special vacuum systemwith integral solvent recovery.

Ø UNIQUE TECHNOLOGY

Due to the consistent modular design, the system can be configured individuallyand easily matched to the constructional circumstances and specificrequirements. The heart of the Glatt vertical granulator is the patented "Z"-shaped rotor blade.This and various product-optimized chopper designs are theresult of many years of successful development and cooperation with theJapanese specialist, Powrex.

Figure 17Patented "Z"-rotor(10)

Ø CYLINDRICAL WORKING VESSEL

It is used for non-sticky products in campaign production.

http://www.pharmainfo.net/fluidized-bed-dryer



Figure 18Glatt vertical granulator with cylindrical working vessel(10)

Ø CONICAL WORKING VESSEL

It is used for sticky products and similar processes with identical accessoryconfigurations.

Figure 19 Glatt vertical granulator with conical working vessel(10)

Ø SIMPLE HANDLING

It can easily be incorporated into horizontal or vertical product flow. The verticalgranulator can be filled manually by means of containers with lift and transporterdevices (or charging stations) or pneumatically by means of suction conveyorsystems. The granulate is discharged from the working vessel into a fluid bedmachine or a container, either gravimetrically or by means of pneumaticconveyors. A GSF rotor mill is often used downstream in order to achieve ahomogeneous granulate spectrum.

Ø USER-FRIENDLY CONTROL SYSTEM



Glatt offers the customized EcoView and MegaView control systems with simple,logically designed operator guidances, clear process visualizations as well asdetailed and informative process documentation. Qualification and validation ofthe control systems are possible up to GAMP 4.All control systems are designed in-house by Glatt based on hardware andsoftware that has become established throughout the world.Advantages are long-term investment security, superior plant availability, andimmediate and rapid support.

Figure 20Glatt vertical granulator(10)

Ø THE VG PRO DESIGN

Figure 21 Underside of VG cover with recessed washing nozzles and

stainless steel CIP filters(10)

The advantage of VGPROdesign includes:-

·Globally unique 12 bar pressure shock resistance.

·Contained design.

·New design and special materials for low weight.

·Pneumatic sealing with Glatt-C flanges.

·No need for explosion protection measures between fluid bed dryer and vertical



granulator.

·Confirms to ATEX standards with CE labels or EC Manufacturer's Declarations(for partial machines).

·Can be fitted through-the-wall - clean separation of production and equipment.Maintenance and service work can be carried out on the unit during productionand without bringing maintenance personnel into the GMP area.

·Suitable for WIP/CIP

* The figure or table represented to express the comparison or concept which isnot available in any of the reference book. It is drawn by our self to simplify theconcept.

4. REFERENCES

1. www.niropharma.com/granulation/history/14th January 2007

2. www.ptemagazine.com/14th January 2007,(pharmaceutical techno l og y,Europe, November 2004)

3. Aulton M.E., second Edition “Granulation”, Pharmaceutics “The science of

dosage form design, Churchill Livingstone, Edinburgh, Second edition,181,187,188, 2002

4.Swarbrick J, Boylan J.C, “Granulation”, Encyclopedia

of pharmaceutical technology, Marcel Dekker INC, New York, Volume- 7, 121-123, 1992

5. Dilip M. Parikh, “Theory of Granulation”, Handbook of PharmaceuticalGranulation Technology, Marcel Dekker INC, New York , 8,15,16,152, 1997

6. Dilip M. Parikh, “High Shear Mixer Granulators”, Handbook ofPharmaceutical Granulation Technology, Marcel Dekker INC, New York, 165-181, 1997

7. www.bhagwatipharma.co.in/22th January 2007

8. www.samsmachines.com/22th January 2007

9. www.niroinc.com/22th January 2007

10. www.glatt.com/22th January 2007

11. www.niropharma.com/22th January 2007

12. S.J.Carter, ”Powder flow and Compaction”, Cooper and Gunn’s Tutorial

pharmacy, 6th edition, CBS publishers & distributors, New Delhi, 217, 2000

13. Leon Lachman, Herbert A. Liberman, Joseph L. Kanig, ”Tablets”, The Theory

and Practice of Industrial Pharmacy, 3rd edition, Varghese publishing house,Bombay, 318-320, 1991

14. Rumpf H., ”The Strength of Granules and agglomerates ”Agglomeration(W.A.Knepper,ed.), Interscince publisers, New york,379-419, 1958

15. Rumpf H., ”The Strength of Granules and agglomerates ”Agglomeration(W.A.Knepper,ed.), John Wiley, New york, 97-129, 1962

16. Ghebre-Sellassie I., “Mechanism of Pellet Formation and Growth”,Pharmaceutical Pelletization Technology, (I. Ghebre-Sellassie,ed.), MarcelDekker,Inc.,New York, vol.37,123-143, 1989

17.Summers M.P., ”Granulation”, Pharmaceutics, The science of Dosage



Forms Design, (M.E.Aulton,ed.), Churchill livingstone, New York,616-628, 1988

18. Worts O.M., Rev.Port.Farm.23, 438-449, 1973

19. capes C.E., ” Size Enlargement Methods and Equipment”, Handbook ofpowder Science and Technology, (M.E. Fayed and L. Otten, eds.), VanNostrad Reinhold, new York, 230-251, 1984

20. www.niropharma.com/design/High shear mixer granulator/9th march 2007

21. www.cronimosr.com/product/High shear mixer granulator/9th march 2007

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