fluidization technologies: aerodynamic principles and process engineering

Fluidization Technologies: Aerodynamic Principlesand Process Engineering

RAHUL DIXIT, SHIVANAND PUTHLI

Drug Delivery Division, Panacea Biotec Ltd., Samarpan Complex, Chakala, Andheri (East), Mumbai 400 099,Maharashtra, India

Received 9 August 2008; revised 14 January 2009; accepted 15 January 2009

Published online 1 April 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21722

CorrespondeFax: 91-22-2838

Journal of Pharm

� 2009 Wiley-Liss

ABSTRACT: The concept of fluidization has been adapted to different unit processes ofpharmaceutical product development. Till date a lot of improvements have been made inthe engineering design to achieve superior process performance. This review is focusedon the fundamental principles of aerodynamics and hydrodynamics associated with thefluidization technologies. Fluid-bed coating, fluidized bed granulation, rotor processing,hot melt granulation, electrostatic coating, supercritical fluid based fluidized bedtechnology are highlighted. Developments in the design of processing equipmentshave been explicitly elucidated. This article also discusses processing problems fromthe operator’s perspective along with latest developments in the application of theseprinciples. � 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci

98:3933–3960, 2009

Keywords: fluidization; fluid bed; aerod
ynamics; coating; granulation; spheronization
INTRODUCTION

Process analytical technology (PAT) has beenadvocated by the USFDA1 which is defined as asystem for designing, analyzing, and controllingmanufacturing through timely measurements(i.e., during processing) of critical quality andperformance attributes of raw and in-processmaterials and processes with the goal of ensuringfinal product quality. The objective is to helpmanufacturers develop and implement new effi-cient tools for use during pharmaceutical devel-opment, manufacturing, and quality assurance

nce to: S. Puthli (Telephone: 91-22-28386987;6955; E-mail: [email protected])

aceutical Sciences, Vol. 98, 3933–3960 (2009)

, Inc. and the American Pharmacists Association

JOURNAL OF PHARM

while maintaining or improving the current levelof product quality assurance. Basically, it laysemphasis on understanding a process in details.PAT includes the physical process measurementsof a fluid-bed granulator in an integrated manner.International Conference on Harmonization(ICH) regulatory guidelines (namely ICH Q8and ICH Q9)2,3 support the pharmaceuticalindustry to apply scientific and risk basedapproaches to the development of a product andmanufacturing processes. The ICH Q8 guidelineon Pharmaceutical Development defines thedesign space as ‘‘multidimensional combinationand interaction of input variables and processparameters that have been demonstrated toprovide assurance of quality.’’

Amongst the different unit processes in pharma-ceutical product development; fluidization techno-logy has been exploited in coating, conveying,

ACEUTICAL SCIENCES, VOL. 98, NO. 11, NOVEMBER 2009 3933

3934 DIXIT AND PUTHLI

drying, and granulation processes. It has beenobserved that these applications of fluid beds seemstill to rely majorly on user experience rather thanon the knowledge of basic phenomena of theprocesses. The scaling-up of these fluidized bedshas been an important area in the processdevelopment. Simplified small-scale systemsmay allow novel tools for understanding, forexample, the effects of physicochemical back-ground, and the surface properties of materialson their behavior in almost ‘‘chaotic’’ fluid-bedprocesses. Before considering each of the fluidiza-tion processes, it would be worthwhile to look atthe fundamental principles upon which thetechnologies are based.

Different parameters influence the fluidizationcharacteristics and they can be classified into twomajor groups comprised of independent variablesand dependent variables. Independent variablesinclude fluid properties (e.g., density, viscosity,relative humidity), particle characteristics (e.g.,density, size, shape, distribution, surface rough-ness, and porosity) and equipment related such asdirection of fluid flow, distributor plate design,vessel geometry, operating velocity, centrifugalforce, temperature, pressure, type of nozzle, etc.The dependent variables are basically capillaryforces, minimum fluidization velocity, electro-static forces, bed voltage, van der Waals forces,etc.

Coating of pharmaceutical dosage forms eitherfor improving the stability of pharmaceuticalproduct or for aesthetics or for modification ofdrug release can be achieved by using differenttypes of equipment and one of the options isfluidized bed coating. In this case the substrate(particle or pellet or capsule, etc.) is in the state offluidization while the coating solution is sprayedonto it. The process is faster than other conven-tional methods of coating such as pan coating,perforated pan coating, and others. A lot ofliterature can be found that have utilized thefluid-bed coating. Improvement in dissolution ofpoorly soluble drugs has many challenges. Soliddispersions of silymarin with polyvinylpyrroli-done in ethyl alcohol solution were loaded onto thenonpareil pellets using a fluid-bed coater.4 Flui-dized bed coating technique has also been usedto achieve varying types of drug release profiles.A S-shape drug release profile with an initiallag time and controlled release thereafter wasachieved by coating in a fluid-bed coater.5 Fluid-bed coating is used in variety of pharmaceuticalapplications like taste masking, modified release

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 11, NOVEMBER 20

dosage forms like controlled and sustainedrelease, enteric coating, and prolonged releasesystems. Powders, tablets, and pellets have beensubjected to coating in fluid-bed coaters. A one-step fluidized bed coating technology has beenemployed for enhancement of dissolution oflansoprazole with polyvinylpyrrolidone solid dis-persion pellets.6

Drying is invariably understood to be theremoval of moisture or solvent from a system.The drying process essentially involves heattransfer and mass transfer phenomena. Heat istransferred to the product to evaporate the liquid,and mass is transferred as vapor in the surround-ing gas. Different types of equipment are usedfor drying process. Fluid-bed drying is employedwidely in many of the pharmaceutical operationsdue to marked reduction in process times ascompared to the traditional drying process ofusing drum or tray dryers. In the drying opera-tion, the transfer of heat in the fluid bed takesplace by convection (the transfer of heat from onepoint to another within a fluid either gas, solid,liquid, by the mixing of one portion of the fluidwith another). The removal of moisture from aproduct granulated in the fluid-bed granulator orin other equipment fundamentally removes theadded water or solvent. In pharmaceuticals, theunit process of drying is very commonly encoun-tered during solvent based granulation opera-tions, solvent based coating operations.7–9 Theproperties of granules and tablets obtained by twodifferent techniques of drying namely fluid-bedand microwave-vacuum drying have been eval-uated.10 Many of the pharmaceutical activeshave unpleasant organoleptic properties. Thusfor products that are intended to be dissolved ordisintegrated in the mouth needs to have aformulation that would mask the unpleasanttaste. Fluid-bed technology has been exploredfor obtaining such formulations.11–13

Fluid-bed coating has been extended not only totablets but also in pellets, the later havingadvantages of being a multi-unit dosage form.14

pH dependent coating using acrylate polymershave been employed.15 Centrifugal granulationmethod has been employed to prepare Ofloxacinpellets which were later subjected to fluid-bedcoating for sustained release of the drug.16 Theprocess has also been used to modify the absorp-tion window of actives in the gastrointestinaltract; an example is ranitidine hydrochloridewhich was processed by modified fluid-bed coatingto improve its oral bioavailability.17

09 DOI 10.1002/jps

FLUIDIZATION TECHNOLOGIES 3935

FUNDAMENTAL PRINCIPLES OFFLUIDIZATION TECHNOLOGY

Fluidization Principle: Classification Schemesfor Powders

The term ‘‘fluidized bed’’ was coined due to the factthat a fluidized bed presents similar properties toa fluid because of the high agitation in the system.In a fluidization bed, the fluidization medium isalways comprised of solid particles. The fluidizingmedium is any fluid: gas, liquid, or gas and liquid.In our discussions, we shall consider only gas (airin particular) since this is extensively used inpharmaceutical applications. Generally, the flui-dizing fluid moves upward thereby counteractingthe gravitational force acting on the bed of solidparticulates. In pharmaceutical products we comeacross different types of solids. Broadly, pharma-ceutical powders can be considered as fluffy ordense. This characteristic feature is imparted tothe solid by virtue of the bulk or apparent densityof the material. Bulk density of a material isinfluenced by size, shape, and cohesion of parti-cles. Thus, larger particles leaving space leads tolower bulk density than smaller size particleswhich pack closely resulting in smaller spaces.The density of powders affects a number ofpharmaceutical applications like solid flow, mix-ing, and tabletting. The type of fluidization for airfluidized beds is related to the properties of the airand the solid substance in consideration. In agas fluidized bed, the quality of fluidization isinfluenced by the bubbles moving through thedense particulate phase. Thus, it is important todefine the types of fluidization on the basis of theproperties of the gas–solid systems. In literature,most of the data are drawn from studies on aparticular class of gas–solid system and thenextrapolated to another group or class. This couldhave an undesirable effect during scale-up andmight result in the failure of the system. Geldartreported these in his research18,19 in which heattributed the observations to the classification ofdifferent classes of powders. Geldart20 has basi-cally classified powders that have similar proper-ties into four groups and designated them asgroup A, B, C, and D. The groups are character-ized by the difference in density between thefluidizing gas (i.e., the air and solid in considera-tion) and the mean particle size. Out of these fourgroups, the two extreme groups are Group C solidsthat are difficult to fluidize and Group D which isspoutable. Groups A and B are suitable for the

DOI 10.1002/jps JOURNA

purpose of fluidization. Moreover, Group Apowders have dense phase expansion after mini-mum fluidization but prior to the commencementof bubbling, whereas Group B powders exhibitbubbling at the minimum fluidization velocityitself. The Group A powders are often referred toas ‘‘aeratable’’ powders and Group B powders as‘‘sand-like’’ solids. Geldart has developed numer-ical criteria to differentiate Group A, B, and Dpowders. The numerical criteria for solid particlesize (dp), density (rs), and fluid density (rf) areexpressed as follows:

ðrs � rf Þdp ¼ 225 for group A (1)

Above equation is basically the boundary betweenGroup A and Group B powders

ðrs � rf Þd2p ¼ 106 for group D (2)

Eq. (2) is the boundary between Group B andGroup D powders. Density is expressed in gramsper cubic centimeter and the particle diameter(dp) in micrometers. There is no equation proposedfor the boundary line between Group A and GroupC powders. Amongst the different classificationsystems, the Geldart group concept has beenwell recognized and is often referred to in theliterature, even though several other criteriabased on similar concepts have been propagated.Molerus has proposed criteria to group solids bytaking into account the inter-particulate force aswell as the drag exerted by the gas on theparticle.21 Clark et al. devised dimensionlessnumbers for the powder groups of Geldart.22

The classification scheme for powders is generallybased on the hydrodynamic characteristics orthe fluidization properties of solids with air atambient temperature. Saxena and Ganzha23

found that a particle that is larger according tohydrodynamics classification can be smaller interms of thermal properties. They suggested thata solid should be classified by considering bothhydrodynamic and thermal characteristics. Thissystem takes into account the heat transfercorrelations and the models for large particles.

Fluidization Principle: Terminal and MinimumFluidization Velocities

Terminal velocity also referred as free-fall velocityor settling velocity of a particle in a fluidized bed ofuniform size is the maximum allowable velocity foroperation. This is the air velocity over which drag-ging or transportation of the particles (pneumatic

L OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 11, NOVEMBER 2009


conveying) occurs. The terminal velocity of thesmallest particle in a polydisperse particle systemlimits the operating range of velocity. It should benoted that the terminal velocity of the smallestparticle may be just equal to or even less thanthe minimum fluidization velocity of the largestparticle. In such situations, the carryover of fineswill take place while the largest particles arefluidized or are kept in a fixed bed condition.Further, particles having dimensions between thetwo size extremes will be in a state of fluidization.Consider a particle of volume Vp and density rp

that is moving in a flowing fluid of velocity Uf. Therelative velocity (Ur) is given by the equation:

Ur ¼ Up � Uf (3)

where Up is the particle velocity. Consideringthe motion in one dimension (i.e., movementonly the vertical upward flow), the rate of changein the momentum of the particle, according toNewton’s second law can be given as follows:

Vprp

dUp

dt¼ �ðFD þ FBÞ þ Fg (4)

where the drag force

FD ¼ ApCDð0:5rf U2f Þ (5)

The buoyant force

FB ¼ Vprgg (6)

and the gravitational force

Fg ¼ Vprgg (7)

When the fluid velocity (Uf) is constant,

dUr

dt¼ dUp

dt(8)

and the terminal velocity

dUp

dt¼ 0 (9)

In the case of a spherical particle, Eq. (4) can bewritten to solve for Uf (which equals Up or Ut). Ur

is zero when the particle is just entrained orcarried by the fluid stream. Eq. (4) for Ut is givenby:

Utdprg

mg

¼ð4=3Þd3

prgðrs � rgÞgCDm2

g

(10)

Eq. (10) can be written using dimensionlessnumbers Ret and Ar:

CD Re2t ¼ 4

3Ar(11)


It is observed in the above equations that theproduct CD Ret is a function of Archimedesnumber and can be estimated if the fluid–particleproperties are known. In case the variation inCD Ret as a function of Ret is known for a knownvalue of Ar, one can find Ret, the equation beingvalid only for a spherical particle. The sphericityfactor is important for a nonspherical solidparticle and CD Ret should be known in terms ofRet and sphericity (ws). Plots of CD Ret and Ret fordifferent values of sphericity can be generatedfrom experimental data. Correlation between thedrag coefficient and particle Reynolds number iscited in literature. The air velocity and powderproperties have also been discussed by otherresearchers.24 Recently studies have been con-ducted on fluidization of nonspherical particles.25

Another important factor in fluidization techno-logy is the minimum fluidization velocity (Umf).Several authors have published models for pre-dicting the Umf in different conditions.26–32 Theequation for Umf is described as follows.

Umf ¼ðrp � rgÞ0:934g0:934d1:8

p

111m0:87r0:066g

ðm=sÞ;

dp < 100mm

(12)

Eq. (13) is used for particles larger than 100 mm

Umf ¼mg

rgdvfð1135:7 þ 0:0408 ArÞ1=2

� 33:7g ðm=sÞ;

dp > 100mm

(13)

where rg is the gas density (kg/m3), rp is theparticle density (kg/m3), dp is the particle dia-meter (m), dv is the diameter of the equivalentsphere (m), and mg is the gas viscosity (kg/m s).

The fluid-bed system is a complex unit opera-tion, mainly because the trajectories of particlesare unpredictable. But this phenomena has foundits place in numerous applications because of itspeculiar properties and different behavior such aslimited pressure drop, homogeneity of tempera-ture, rapid heat and mass transfer and the flowrates can be controlled relatively easily. Fluidiza-tion, by its principle, appears to be a segrega-tionist system that must be well designed andengineered in order to achieve homogeneity.Materials having a large size distribution havetendency of separation at velocities close to theUmf. In this case, Geldart suggests the use ofanother parameter referred as overall fluidizing

09 DOI 10.1002/jps


velocity Ucf at which all particles are fullysupported. The equation for the same is given as:

Ucf ¼ SxiUmfi ðm=sÞ (14)

where Umfi and Sxi refer to velocity and thefraction of particles with size dpi.

The density and apparent specific weight isgiven by Eq. (15), neglecting the air density:

rapp ¼ ð1 � "Þrp ðkg=m3Þ (15)

The apparent viscosity proposed by Kunitz can bewritten as:

mapp ¼ 1 þ 0:5ð1 � "Þ"4

ðkg=m sÞ (16)

The pressure drop in the cylindrical fluid bed andthe case of a laminar flow is given by Poiseulleequation:

Dp ¼32mappUH

gD2ðPaÞ (17)

Judicious use of these properties and character-istics could help in the design of an efficient fluidbed for coating system. The velocity, Umf, thatleads to a stable fluid bed Figure 1V, is used forprocesses such as drying, coating and granulation.We can have three cases:

Case 1: When the approach velocity or superficialvelocity is much smaller than the minimizedfluidization velocity. This gives the fixed bed.

Figure 1. Various configurations of fluid bed: (I)Fused bed, (II) Expansion, (III) Channeling, (IV) Slug-ging, (V) Stable fluid bed, and (VI) Conveying type.


Case 2: When the approach velocity is inter-mediate between the minimum fluidizationvelocity and the terminal velocity the fluidizedbed is obtained.Case 3: In this case when the approach velocity ismuch greater than the particle terminal velocity;a pneumatically mobilized bed is obtained.

The fluid (air) flowing through a bed of particlesin a tube exerts a drag force upon the particlesresulting in a pressure drop across the bed. Thispressure drop magnifies as the fluid’s approachvelocity is increased. Fluid flowing in upwarddirection in an unrestrained bed causes a condi-tion where with increasing fluid velocity, the dragforces will cause the bed to expand. As a result,this allows the particles to offer less resistance tofluid flow. When this drag force is sufficient tosupport the weight of the particles in the bed, thebed is said to be in the state of fluidization.Eventually, the pressure drop across the bed (Dp)remains constant and equal to the effective weightof the bed per unit area. The equation for this isgiven below

Dp ¼ m

rpsbðrp � rf Þ

� �g (18)

where m is the mass of the particle, rp is thedensity of particle, Sb is the cross-sectional area ofthe bed, rf is the fluid density, and g is thegravitational force.

When the air velocity is increased beyond thatrequired to bring the bed to a fluidized condition,that is, beyond the minimum fluidization velocity,the bed will start to ‘‘bubble.’’ This typicalphenomenon is termed as aggregative fluidiza-tion. By further increasing the air velocity thebubbles would grow so large that they wouldnearly or completely fill the cross-section of thetube pushing slugs of particles thus giving rise towhat is called as slugging bed. One can have twosituations, one in which the fluid under consid-eration is more dense (like a gas at high staticpressure of a liquid) and the second where theparticles are very fine (20–100 mm) and less dense(<1400 kg m�3). In both the cases the bed would beable to sustain a certain degree of stable expan-sion, known as particulate fluidization. It shouldbe noted that the substrate bed would remainstable until the Umf had been exceeded by a factorof 2 or 3. In contrast, when gas is employed tofluidized a bed, the bed would collapse and againstart to bubble with further increase in gas



velocity. Fine cohesive powders are very difficultto fluidize because the inter-particulate forces aregreater than the gravitational force. In this case,the particles tend to stick to each other and the airhas to pass through creating channels through it.

A fluidized bed system and its applications indifferent pharmaceutical unit operations will beconsidered next.

FLUIDIZED BED COATING

Coating is an important unit operation in thepharmaceutical industry. There are a number ofapplications of coating, including drug layering,modified release coating, physical and chemicalprotection, aesthetic purposes, taste masking, andenhanced identification of drugs.33–36 The basicapparatus used for different applications (granu-lation, coating, agglomeration and drying) is thesame with different attachments made in thebasic unit. There are three phases present in afluid bed: solid (particles), liquid (liquid coatingmaterials) and gas (the fluidizing air). During thecoating operation, there are a number of activitiestaking place at micro level, due to interactionbetween these phases. In a fluid-bed coatingoperation, particles to be coated are first intro-duced into the cell and fluidized by an air current.The type and quality of air used is important. Thehumidity of air would determine the efficiency ofthe operation and the temperature would influ-ence the drying time. The coating material ispumped through a nozzle and sprayed on theparticles. During this process, there is a homo-geneous layering of the coating material on theparticles. However there is also a tendency forparticles to agglomerate to each other. After theparticle surface is wetted by the coating material,there is always a competition between continuouslayering of the coating material (following thewetting and drying cycle) on the dried particle onone hand and agglomeration of wetted particles onthe other hand. Some of the activities taking placeeither independently or simultaneously are forexample the particle dynamics where the particlesare suspended in the air in coating chamber. Thecoating material is sprayed as droplets with theaim to increase the probability of particle-dropletimpacts but droplets can easily be dried (heattransfer) before the collision with the particle.The droplets then spread on the particle surfacefollowed by flattening and adhesion of the dropleton the particle (mass transfer). This can be


different in the coating of solution or latexdispersions as the case may be. The coalescenceof droplets occurs on the particle surface beforedrying (heat transfer) to form a uniform layer.After several wetting and drying cycles, acontinuous film is formed, with a controlledthickness and a composition depending on thematerials used. It should however be noted thatthe tendency for agglomeration between two orseveral particles is high at this stage. The successof coating depends on spreading of the droplet onparticle surface after collision. The significantfunction in the whole process is the wettingenergy.37 The wettability of powders has beendiscussed by different research groups.38,39 Thewetting energy depends on the contact anglebetween the three phases present (solid, liquid,and air). Further the contact angle depends onchemical and physical characteristics of the liquidand the particle surface (hygroscopicity androughness). The wetting energy can be expressedas a wetting coefficient Wm (assuming a flat,homogeneous, isotropic, and nondeformed sur-face) as given in equation:

Wm ¼ gSV � glV � gSl ðJÞ (19)

where gSV is the interfacial tension between solidand vapor (J), gSl is the interfacial tensionbetween solid and liquid (J), and glV is theinterfacial tension between liquid and vapor (J).A liquid can wet a surface if the wetting modulusis larger than 0 (Wm> 0). The performance offluidized system thus should take into account allthese aspects of the process. The coating perfor-mance is defined as coating efficiency,40 Ec

Ec ¼Wc

WcsDm (20)

where Wc is the deposited mass of the coating, Wcs

is the mass of the coating solution in kg, and Dm isthe coating solution dry mater content in kg/kg. Ec

is a type of material efficiency and its expressionshows that there is no information about theenergy balance or the quality of the resultingcapsules. The suggestion here is that coatingperformance be considered from general point ofview and that at least four efficiencies be definedas given below.

Ec, the material efficiency, given above as acoating efficiency. Ee, the energy efficiency. Eq,the quality efficiency, whose definition cannotbe generalized since it is related to a requiredproperty. Ep, the productivity efficiency, which issimply defined as the total amount of coating

09 DOI 10.1002/jps


material per hours. It is in fact the most importantfactor for scale up or industrial application. A gooddefinition of performance criteria is essentialfor improvement assessment. The best way toimprove a given system today is by design andmodeling followed by automation.41

Figure 3. Different variations of fluidization technol-ogy: Top spray (A), Bottom spray (B), Wurster processor(C) and Rotor with disk (D).

THE WURSTER TECHNOLOGY

The basic technology of fluidization was firstintroduced by Dale E. Wurster with the concept ofbottom spray approach.42 The patents based onthis were the first ones to revolutionize the use offluidized bed technology especially in the Phar-maceutical arena. Some of the first patents ofWurster as the inventor on the fluid-bed techno-logy are US 2,648,609 (August 11, 1953): methodof applying coatings to edible tablets or the likeand US 2,799,241 (July 15, 1957): means forapplying Coatings to tablets or like. The classicaldesign of the invention is reproduced from thepatent in Figure 2. Later a lot of modifications in

Figure 2. The first patent that proposed the Wursterfluidization technique (Source: US patent 2,648,609).


the basic equipment led to development of varioustypes of fluidized bed equipments as seen inFigure 3. The utility of each of the equipment isspecific for example the top spray and rotary withtop spray is used for granulation, bottom sprayand Wurster processor essentially for coating. Thebottom spray system considerably increases thecollision between particles and droplets resultingin a larger coating material efficiency andreduction in spray drying (reduction in dustformation). This type of fluidized bed was veryefficient for tablet and pellet coating. But forsmaller particles, the risk of agglomeration washigh because of the high concentration of wetparticles. The process has been studied in detailsand has identified ten micro-level sequentialprocesses namely particle motion, atomization,droplet–particle collision, droplet impact andadherence, droplet impact and spreading, infil-tration, drying, film formation, layering and inter-particle agglomeration.43 It is also emphasizedthat the process is most dependent upon drying,droplet impact and adherence, droplet impact andspreading, and inter-particle agglomeration. Thisis exemplified in Figure 4. As can be seen, duringtheir flight along the axis, droplets are deposited


Figure 4. Diagrammatic representation of a Wurstersystem with different stages in particle coating (a microlevel approach). Key: The dragging zone or spoutingzone (I) where particles are sucked by the air into theinsert cylinder, the inner cylinder zone (II) is wherethe particles are transported via pneumatic conveying,the annular zone (III) where particles fall down towardsthe bottom of the chamber and the tampon zone(IV) where particles are moving slowly in successivejumps towards the spouting zone area. Stages: (1) par-ticle motion, (2) atomization, (3) droplet-particle colli-sion, (4) droplet impact and adherence, (5) dropletimpact and spreading, (6) infiltration, (7) drying, (8) filmformation, (9) layering, and (10) inter-particle agglom-eration.


on the particles. The impingement efficiency canbe expressed by the following equation:

’ ¼ St

St þ b

� �a

(21)

where St is the Stokes number and a, b areconstants depending on Reynolds number.44

A typical diagrammatic representation ofthe Wurster technology is shown in Figure 4.The bottom insert of spray-Wurster design can beseparated into four parts namely the draggingzone or the spouting zone (I), where the substrateparticles are sucked by the air current to the entryof the insert cylinder. The cores are wetted in thiszone by the sprayed coating liquid. The innercylinder zone (II) is the region where particles aretransported by pneumatic conveying. The dryingprocess takes place in this zone. The annular zone(III) is the zone where particles fall in downwarddirection towards the bottom of the fluidizingchamber. The particles are moving slowly insuccessive jumps towards the spouting zone at thetampon zones (IV). In order to achieve superior


coating, the wetted particles must be dried duringtheir ascent in the central tube. Hence the meandrying time can be considered less than the timenecessary for particle to travel along the centraltube. In case wet particles reach the annular zone,they will tend to stick to each others resulting inagglomeration tendency since they are too closeto each other and their velocity in this zone isrelatively low compared to that in the centraltube. In Wurster technology, particles, pellets,tablets etc are truly air suspended and the energyfor particle circulation is measurable in terms ofdifference in density between the down flowingand upward moving beds. The ‘down bed’ isbasically the weight of the substrate which isbalanced by the upward flow of air to supportthem. The ‘up bed’ consists of weight of particles,energy for acceleration, losses occurring due tofriction of air movement through the partition.While the pressure drop readings across the bedaccount for about 90–95% of the bed weight theremaining 5–10% is transferred to the walls of theequipment and the partition support. There hasbeen a lot of development in the fluidized processtechnology with emphasis on new type ofsprayers, sophisticated nozzles, air filters andair distribution plates which is discussed later inthis manuscript. Some of the important factorsaffecting the fluidization process are highlighted.

Partition Gap

The partition gap may be defined as the verticaldistance between the bottom of partition columnand surface of the air distribution plate. This isidentified as an important factor in determiningthe success of coating of smaller sized particles45

(like mini-tablets and pellets) and was foundto influence the drug release profile of coatedpellets.46 This research finding was attributed toits influence on the flow of pellets into thepartition column and the exposure of pellets tothe coating droplets in the spray zone. Consider-ing that time (t) is taken for a certain pellet load(M) to flow into the pellet collector, the mass flowrate (MFR) can be determined by the equation

MFR ¼ M

t(22)

The MFR increases, reaches a peak and thendecreases with increasing partition gaps influidized bed systems. The partition gap can bevisualized as a passageway for the pellets. Thus

09 DOI 10.1002/jps


when the partition gap is large, there might beinsufficient pressure differential to draw particlesup the partition column. When the partition gapis small the passageway is constricted and theproduct moves at a faster velocity through thepartition gap by what is called the Venturi effect.However, when the partition gap is considerablyreduced, it restricts the passage of pellets.

Material Load

The load of material being coated is also impor-tant. Linear relationship exists between MFR andmaterial load in Wurster coating. This tendency isalso observed in a conical spouted bed wherein thesolid flow rate increases with increased stagnantbed height.47 The increased load probablyincreases the ‘‘hydrostatic pressure’’ which tendsto push the material through the partition gap.The Wurster coating relies on the feeding ofmaterial load to the partition gap for transport, acontributory factor being the sloping air distribu-tion plate. The flow properties of the materialbeing fluidized also plays an important role inparticle transport in Wurster coating.

Dosage Form Size

The MFR is also affected by the substrate particlesize. It has been reported that larger tablets hadlonger cycle times than smaller tablets at thesame conditions in experiments conducted inWurster coater.48 This typical behavior of thesize of dosage form on the MFR can be explainedby Newton’s second law of motion. The lawindicates that acceleration is directly proportionalto the force exerted and inversely proportional tothe mass of the object. Now let us consider smalldosage forms like pellets. In this the smaller sizepellets will have similar MFR as larger pelletsin spite of the higher central acceleration (asexplained by Newton’s second law of motion). Thismay be due to the higher trajectories of smallerpellets at high air flow conditions, causing thematerial to be suspended in air for a longer timebefore completing the cycle. This is good in termsof drying efficiency. However, it may also causethe substrate bed height to decrease excessively,resulting in insufficient pellet flow through thepartition column and also can result in over-wetting. There is one more effect observed inWurster-type systems and that is the air-curtain


effect. As the air flow rate increases it affects airflow peripheral to the spray nozzle and resultingin development of air-curtain effect at theperipheral region of the spray zone. This even-tually prevents the pellets from moving throughthe partition gap. In fact, smaller sized pelletstend to be more affected by this effect and facemore problems in traveling from the peripheralstaging area into the spray zone and partitioncolumn.

Fluid Dynamics

The Air flow and atomization pressure are againtwo significant parameters that can affect theMFR. They are responsible for pneumatic trans-port of the material and the drying of coatedsubstrates respectively. Adequate fluidization isachieved by proper adjustment of air flow.Atomization pressure basically breaks up theliquid spray into small droplets. Very high air flowand atomization pressure may result in attritionof the mass and increased spray-drying effecthence appropriate adjustments are essential toachieve effective coating. Considering the airdistribution plate for bottom spray processor,the area of air directly under the partition columnhas more perforated area than the peripheralregions. This results in a higher central airvelocity through the partition column. Thisfurther leads to a region of low pressure thatdraws in particles by the Venturi effect and liftsparticles up the partition column (up-bed zone), aphenomena according to Bernoulli’s law. Basicallythe particles of the product bed enter the partitioncolumn (referred to as horizontal transport zone)and decelerate in the expansion chamber (thedeceleration zone). The particles then fall out-wards in an inverted U-shape trajectory back ontothe product bed area (called as down-bed zone).Later, the particles reenter the partition columnthough the partition gap. Thus fluid dynamics wasfound to control product quality and productivityin bottom spray fluid-bed coaters.49,50 The flowpattern of the particles are dependant basically onthree factors viz. the cycling time of particles,movement of the particles around the nozzlewhere they are sprayed by the coating solutionand velocity and density of the particles. Thehigher is the drying rate, the shorter is the cyclingtime and the shorter the operating time can befor coating a certain load to a specific degree.Knowledge on the cycling time distribution is



important in order to estimate to what degree ofuniformity the coating can be achieved after aknown time of operation. The concentration ofparticles at the nozzle has a significant effect onthe fluidization operation and the velocity ofparticles in turn affects the degree of attrition ofthe particles. The airflow pattern plays a sig-nificant role in the operation of this process. Thedrying rate including the heat and mass transfercoefficients are dependent on the airflow rate andalso on the contact between the air and particle.The airflow pattern also influences to a largeextent the flow pattern of the particles. Thefraction of stream of air that flows above andacross the distribution plate affects the movementof the particles towards the center.

Droplet Size of Coating Material

The type of spray nozzle used is thus verysignificant. The droplet size may be predicted bythe following equation by Masters51

dg ¼ 585 � 1033ps

Upr

� �

þ 597mpsr

� �0:45 1000Qsol

Qa

� �1:5

ðmÞ (23)

where s is the fluid surface tension (N/m), r isthe fluid density (kg/m3), m is the fluid viscosity(kg/m s), Qsol is the fluid volumetric rate (m3/s), Qa

is the air volumetric flow rate (m3/s), and U is therelative velocity outlet air velocity (m/s).

Drying Cycle

Once the droplets are formed, the main criterion istheir impact with the particles before their drying.The time for evaporation can be employed tocalculate the drying time of the droplets and todefine spraying conditions for a particle collisionbefore the drying of the droplet by the followingequation52

ttotal ¼lr1ðd2

0 � d2c Þ

8KdðTa � TsÞþld2

crpðXc � XfÞ12KdDTav

� �ðsÞ (24)

where dc is the droplet diameter at critical point(m), d0 is the capillary diameter (m), Kd is thethermal conductivity, r1 is the density of liquid(kg/m3), rp is the density of the particle (kg/m3), Xc

is the critical moisture content (%), Xf is the final


moisture content of the dried particle (%), Ta isthe air temperature (8C), Ts is the droplet surfacetemperature (8C), Tav is the average temperature(8C), and l is the latent heat of vaporization(J/kg).

It must be noted that the vapor pressure andReynolds number has been neglected in the aboveequation. Once droplets of the coating substanceare spread on particles, they must dry quickly orelse they will reach the annular area where theycan undergo agglomeration

� 3

4dprp CDrgðug � upÞ2 þ 1 �

rg

rp

� �g

� �¼ 0 (25)

and

Tc ¼Hc

upðSÞ (26)

Ta ¼ Ha

utðSÞ (27)

Td ¼ m

QmsðSÞ (28)

where Hc is the distance covered by particle in thecentral tube (m), Ha is the length of the annularzone (m), M is the total mass of the particle in thesystem (kg), Tc is the residence time in the centraltube (S), Td is the residence time in the draggingzone (m), and Qms is the flow rate in kg/cm.knowledge of the particle velocity and the flowrate in the different areas allows the calculationof different residence time. The velocity in thedragging zone is not constant and can only bederived from mass balance or from the flow rate.The minimum spout flow rate (Eq. 29) is the goodapproximation of the flow rate53

Qms ¼ rp � 5:92

� 10�5 dp

FDc

� �0:05 Di

Dc

� ��2:6

ðkg=sÞ (29)

where dp is the particle diameter (m), Di is theequivalent diameter of the bed (m), Dc is theequivalent diameter of the bed slot (m), and F isthe sphericity of the particle. Gouin has reportedthat spray drying losses increase the productioncosts due to loss in coating material and increasedprocessing times required to reach the samedegree of coating.54

09 DOI 10.1002/jps


EQUIPMENT DESIGN PARAMETERS OFFLUIDIZED BED TECHNOLOGY

Air Flow Pattern

Some undesirable features like particle chipping,fracture and/or attrition are to be avoided in theequipment. It has been observed that impactvelocities greater than 10–20 ft/s are most likelyto cause fractures. Hence, it is also important todesign fluidized bed equipment in a way such asto maximize airflow rates consistent with theseparticle velocity limitations. This can be achievedby the use of partitions of diameters as large aspossible. In order to achieve higher air flow rates,faster application of coating material is madepossible. Further, this dimension is usuallylimited by the ability to properly distributeatomized coating material across the full crosssection of the airlift area. Different equipmentmodifications have been made to improve theefficiency of coating process. The same has beendiagrammatically discussed in Figure 5. Special

Figure 5. Fluidized bed coating equipment config-urations.


air grid designs have been used for productrecirculation. Different types of air flows can beobtained by changing the design of a coatingequipment. For example the application of airgrids with different free areas results in a verticalflow of the product (Type A).55 In this case thepressure drop across the air grid is constant at allplaces leading to a range of air velocities which inturn results in a rolling vertical product move-ment. This movement of solids can be increased bythe use of Wurster columns (as in Type B) throughwhich the particles are conveyed to the top of thebed with a higher air velocity. This process hasbeen widely exploited in coating different phar-maceutical dosage forms. The typical processprevents short-circuiting of particle movementin the bed. Conical fluidized beds results in ahigher gas velocity in the coned section and hencealso in vertical recirculation (Type C). In anothermodification, a horizontal product movement witha superimposed vertical product movement canbe achieved in a typical spherical fluidized bed(Type D, like Huttlin Kugel Fluid bed coater). Thisalso includes an annular air distributor. It can benoted that in all the types of systems the objectiveis to increase the air velocity at the feed nozzle.Further, the coating material is sprayed into thebed by a number of feed nozzles (in large scaleproduction equipment) leading to a better dis-tribution of the coating material while less solidsmixing is required for the same total spray rate.Equipments with a combination of fluidizationand mechanical mixing have also been designed(Type E and Type F) which has been discussed indetails elsewhere in this manuscript.

Partition

In fluidized bed equipment a partition with halfthe diameter of the working chamber appears toafford optimum performance for tablets. In case ofsmaller particle sizes (like powders and pellets)the partition would have diameters ranging fromhalf to two-third of working chamber.

Air distribution Plate Design

The aerodynamics of particles is highly dependanton the type and geometry of the air distributionplate situated at the bottom of the equipment.The pattern of open areas on the plate appears toprovide proper air distribution for different range


Figure 6. The Gill air distribution plate design(Source: http://www.niroinc.com/pharma_systems/fluid_bed_drying.asp).


of products (which varies for powders, granules,pellets and tablets; as the case may be). The largeopenings will carry more air per unit of area ascompared to smaller openings. It should be notedhere that the pressure drop across the plate mustbe the same through the large as well as the smallholes. This difference will be in proportion to thesquare root of the ratios of the diameter of thelarge to the diameter of the small openings. Themain factor that controls fluidizing air distribu-tion is the total pressure drop through the bed ofparticles. A reduction in the total pressure dropfor example, tends to reduce the quantity of airthat can be turned to move horizontally as itleaves the plate. A reduction of this air vectorrestricts the movement of particles toward theairlift. This fact can be explained in terms of thepath lengths, which must be traversed by airentering the working chamber through theperimeter of the plate. It is required that someof this air moves straight up through the down bedso that the particles can be supported in weight-less contact. Further, it is also important that partof the air moves horizontally toward the partitionto provide the transport energy for movingparticles to the airlift. The ratio of air volumesmoving in these two directions is dependent uponthe geometry of the apparatus. Different types ofair distributor plates have been designed such asGill Plate, Precision coater (Niro) and Huttlin’s airdistribution plate.

The Gill Plate

In past, the sandwich-type construction wasemployed in fluid-bed systems. In this typicallya fine screen of 60-325 mesh covered the airdistributor plate which retained the finer productin the container. However, the major drawback ofthis was the challenge to keep the screen and airdistributors clean. To solve this problem, in 1990sthe overlap Gill Plate was introduced.56 This plateprovided excellent air distribution and also therewas no need of the fine screen.

Batch fluid-bed technology for Niro is developedby sister-company Aeromatic-Fielder (Switzer-land and UK). Their systems use Gill PlateTM

air distributor plate (Fig. 6). The Gill plate isextensively employed in continuous fluid-beddryers. Unlike the sandwich-type air distributor,the Gill plate is easier to clean. These nonsiftingGill plate air distributors are typically appro-priate for a unit in which the container is fixed


and product discharge is by gravity or pneumaticmeans (http://www.niroinc.com/food_chemical/batch_fluid_bed_processor.asp).

Precision Coater (Niro)

With reference to the traditional fluidized bedcoater, a large portion of the air flows into the bedaround the column. This allows particles to floodinto area around the spray nozzle by virtue of thehydrostatic head of the bed. The Precision coater57

(GEA-Aeromatic Fielder, Eastleigh Hampshire,UK; presently Niro Inc.) is similar to the Wurstercoater except for its mode of air distribution. Theair distribution plate in the Precision coaterconsists of a perforated plate connected to theSwirl Accelerator (GEA-Aeromatic Fielder). TheSwirl Accelerator functions to swirl and acceleratethe inlet air to impart spinning movement andhigh velocity to particles as they transportthrough the partition column where coating takesplace. This modified process changes fluiddynamics of the particles. Thus in the precisioncoater more amounts of air are directed into thecoating column via an insert plate and the swirlaccelerator as compared to the Wurster coater.This specific design creates a much higher processair speed adjacent to the nozzle and generates alow-pressure zone that sucks particles into thecore of the coating tube. The air with high speedcauses individual particulates to spin allowing amuch more uniform coating. Accelerator insertswith smaller inlet diameters generates higher airvelocities, which increases the pressure differen-tial across the partition gap. However, it mustbe noted that very high air velocities may causeparticles to hit onto the top of the chamber causing

09 DOI 10.1002/jps


attrition. The swirl accelerator generates a rota-tional component to the air stream which whencombined with the high speed of the air streamensures that the individual particles are keptseparate so that it is possible to operate at higherhumid conditions without the risk of agglomera-tion. In the process, evaporation rate is also highersuch that particles are dried and will notagglomerate long before they return to the bedaround the coating tube. Since the partition gap isknown to affect the pressure differential, it hasgreater influence on MFR in precision coatingindicating that the mechanism of transport ofpellets in precision coating is dependent on thepressure differential across the partition gap ascompared to conventional Wurster coating. TheMFR in precision coating is significantly greaterthan that of Wurster coating when the partitiongap is varied. Therefore, precise adjustment ofpartition gap is crucial in controlling MFR inprecision coating than in Wurster coating. Theprocess times are also considerably reducedcompared with traditional coating systems. Theutilization of ‘‘high speed–low pressure’’ zone tosuck the particles into the coating area, enablesthe Precision Coater system to avoid dead areaswith low particle flow.

Huttlin’s Air Distribution Plate

The Huttlin’s air distributor plate is described inUS patent 6,705,025 (Bottom element for a devicefor treating particulate material). A schematic ofthe plate is given in Figure 7 for better under-standing. Basically the plate has apertures orslots that have side walls sloping towards theplane of the bottom, thereby imposing specificmotion to the material while passing the slots.Due to successive tapering of the side walls of theslots in a direction to that side of the bottom, noparticles can enter into a slot and obstruct it. Theslots are curved and extend radially toward a

Figure 7. The Huttlin air distribution plhuettlin.de/fluid_bed.html). The apertures in thof nozzles increase the efficiency of the fluid-b


centre of the bottom. In the equipment there areopenings at the bottom for spray guns.

Air Lift

The travel of air from the perimeter of the platetoward the partition should be horizontal in orderto move particles at a uniform rate from all areasof the bottom of the down flow bed. The airentering through the outer areas of the supportplate will not move toward the air lift unless thatpathway offers less resistance to flow than theshorter path directly upward through the bed.When fluidization is initiated, the particles in thepartition accelerate due to which the bed densitydecreases and the level changes. Thus, althoughthe path length changes, the resistance to the airflow remains same. Lower up bed densities resultin high velocities for the particles. This can beoffset by using reduced air flow rates. However,this is undesirable because it reduces dryingcapacity and also affects the coating rate. In fact,densities lower than the limiting density mayactually be required in order to properly exposethe particles to the atomized spray of coatingmaterial on each pass through the airlift. Thelower densities can be attained by introducing alarger percentage of the total airflow through theportion of the support plate which is presentimmediately below the partitioned zone. In case ofsmall particles, one requires a low density in theairlift at the expense of increased particle velocity.A balance between particle velocities and uni-formity of applied coating is the key to properequipment design. Particle circulation rates isgoverned by density of beds (down and up), timefor down flow of particles and cross-sectional areasof zones.

Spray Nozzles

As found by numerous authors, a nozzle jet in afluidized bed shows many similarities to a free

ate design (Source: http://www.oystar.e plate along with the typical adjustmented processor.



jet.58,59 The siphon type nozzle systems requiringatomizing air were used when applying coatingsolutions to large particles like granules andtablets. However the limitation in these nozzleswere the relatively low application rates and theamount of atomizing air required to properlyatomize the coating solution. The demand forincreased rate from air atomizing nozzles wasapparent when faster cycle times for productswere desired. The need for greater capacitieswarrant larger air orifices in the nozzle and higheratomizing air pressure required to atomize thecoating solution. Further, the large volumes ofhigh velocity atomizing air tends to disturb theupward movement of the particles. Also largerliquid orifices are ineffective in properly atomizingthe coating solution. These problems were over-come by the use of airless spray equipment.

A spray can be considered as a zone of liquiddroplets in a gas. The objective of spraying is toaugment the surface area of a given mass of liquid,in order to disperse it over the substrate area.Three general methods have been studied forspraying through a nozzle, namely (a) liquid issucked by a pressure drop created over the area ofnozzle cap and later compressed air atomizes theliquid stream by disintegrating it with air jet,(b) the compressed air drives the liquid throughthe orifice and then the surface tension createsdroplets, or (c) pressure streams of two liquidsimpinge upon each other, thus giving rise to ahighly dispersed uniform spray. A range of nozzlesdesigns are available from which one can choosedepending on the applicability. Pressure nozzletype of system is where the fluid which is underpressure is broken up by its inherent instabilityand its impact on another jet, or on a fixed plate,on the atmosphere. Another type is the Rotatingnozzle (referred as rotary atomizer) where thefluid is fed at a low pressure to the center of arapidly rotating disk, and the centrifugal forcebreaks up the fluid. This nozzle type is usedmainly in a spray drying application. Anothervariety is airless spray nozzles in which the fluid isseparated into two streams. The two fluid streamsare later brought back together at the nozzleorifice, where upon impingement, they formdroplets. Gas atomizing nozzle (two-fluid nozzleor binary nozzle) is another type where the liquidis atomized by compressed air. Further, thesenozzles are available as either single-port ormultiport varieties. Whiles the single-port is goodfor small batch sizes, for larger batches one needsto go for the multi-port options. Three distinct


phases of spray are observed in these air atomizednozzles. In the first phase, gas undergoes adia-batic expansion (from relatively higher pressureat the nozzle to that at the fluidized bed chamber).The air is subjected to Joule-Thompson effect andits temperature drops. In the phase two, the liquidtransforms into discrete droplets. In the lastphase, the drops travel to the substrate or getscompletely dried in the fluidized chamber. Both,the spray pattern required and the spray angleare adjusted by regulation of the air cap. Glatt hasdevised a 3-head single arm and six-port singlearm nozzles. GEA process Engineering Ltd (Nirodivision) has developed an internal mixing twofluid nozzle by systematic variation of internalparts. This nozzle is an internal mixing two-fluidnozzle specially designed for pharmaceuticalapplications such as production of inhalableparticles. The advantage is that this nozzle hasa relatively higher capacity compared to existingtwo-fluid nozzles. It has the ability to produce finedroplets with a average particle size below 10 mm.The reader is referred to different studiesconducted on spray nozzles in literature.60–64

TOP SPRAY FLUID-BED PROCESSING

This is also referred as down spray coating. In theequipment used for top spray, the expansionchamber is extended allowing powder to remainfluidized for longer duration and to move with ahigher velocity so that agglomeration is mini-mized. The expansion chamber is generallyconical in shape which permits uniform decelera-tion of the air stream. The spray nozzle is adjustedlow in the expansion chamber such that coatingmaterials impinge on the fluidized particles ashort distance from the nozzle. This reducestendency of droplet spray drying and providesfor longer subsequent drying of the coatedparticles. The granules formed by the top sprayfluidized bed granulation method are generallynot highly spherical and have comparativelylower densities.65 Successful scale-up of granula-tion processes using top spray fluid-bed granula-tion process has been demonstrated66,67 andvarious process aspects have been discussed indifferent research papers.68–72 The top-sprayfluid-bed granulation systems has the disadvan-tage of internal classification like mechanicalmixers. At a given fluidization air velocity, aspecific particle size window is determinedbetween the size which is blown off73 and that

09 DOI 10.1002/jps


which cannot be fluidized.74 The operating‘‘fluidization’’ window will expand upward whenthe bed cross section widens, since fluidization ofcoarse particles is promoted. In fluidized bedgranulation, due to settling nature of coarsergranules (which then do not resurface to initiatebinder loading) the process is robust in obtaininggranules with limited variability. When a batchfluid-bed granulation is considered, the productsize is almost given by the boundary between the‘‘settling’’ and ‘‘fluidization’’ zones at a given gasvelocity. This is one of the key elements why fluid-bed granulators are preferred in industry.

FLUIDIZED BED GRANULATION

The primary objectives of granulation in thepharmaceutical context are to improve powderflow and compaction behavior before tabletting,and to ensure composition uniformity. Fluidizedbed granulation is a process by which granules areproduced in single equipment wherein the bindersolution is sprayed on to a powder bed which isin the fluidized state. It is sometimes referred asone-pot system. The fluidized bed granulation is acomplex process involving manifold process vari-ables and three concurrent rate processes (a)wetting and nucleation, (b) consolidation andgrowth, and (c) breakage and attrition. Wetgranulation technology is a size enlargementprocess of converting small size solid particles(typically powders) into larger size agglomeratesto generate a specific size with the aim ofimproving flowability and to produce a powderwith specific properties such as desired dissolu-tion rate, granule strength and apparent bulkdensity.75,76 It should be noted that the rate ofgranule growth by agglomeration is directlyrelated to the collision frequency between theparticles present in the granulator, and thefraction of collisions that are successful, that is,the fraction of collisions that lead to coalescerather than rebound.77 Thus for a collision to besuccessful the particles must come in contact witheach other by a binder-wet region, and the viscousbinder layer in this region must be able todissipate the kinetic energy of the particles.

The scale-up of granulation in a fluid-bedsystem requires a fine understanding of theequipment functionality, excipient interactions,theoretical aspect of fluidization, and identifica-tion of critical variables that affect the process ofagglomeration. The fluid-bed granulation process


is greatly affected by water in both vapor andliquid form. Wetting of particles is essentialphenomena needed to form liquid and solid bondsbetween the particles that enable the growth ofgranules.78 However, if the moisture in theprocess is too high, granule growth can beexcessive and the bed can even collapse due tothe poor fluidizing capacity of the wettedmass.79,80 Lipsanen et al.81 have studied theinfluence of various relative humidity levels andfluidization modes on the particle-size of finishedgranules. With the importance of process analy-tical technology, the on-line and at-line measure-ments using suitable probes have beenincorporated in fluid-bed granulation.82 Experi-ments of fluid-bed granulations at microscalelevels and small scale batch coatings have beenstudied.83,84

Fluid-bed rotogranulation can produce spheri-cal and dense pellets in a hermetic single potprocessor, as compared to the multi-step extru-sion–spheronization technique. The overall man-ufacturing time required is generally shortenedand manual material handling considerablyreduced. Some of the important factors that needto be considered are fluidizing air flow rate, gapspace between the rotor disc and the unit wall,disc velocity, surface morphology of disk, flow rateof binder solution, atomization pressure and inletair temperature. Operating variables and mate-rial properties which influence the final producthave also been studied.85 General fundamentalproperties of product obtained by using thefluidized bed granulation technique have alsobeen studied.86 Research groups have conductedstudies on optimization and scale-up of granula-tions using fluid-bed granulators.87–89

FLUIDIZED ROTOR PROCESSOR:GRANULATION AND SPHERONIZATION

The rotary fluidized bed granulator differs fromthe conventional fluid-bed processor in that theair distribution plate is substituted by a solidrotating disk in the fluidizing chamber. The rotaryprocessor can be considered as a hybrid version ofa fluidized bed and a spheronizer. It is referred bydifferent names like the rotary processor,90 rotaryfluidized bed,91 rotary fluid-bed granulator,92

rotor fluidized bed granulator,93 or fluid-bedroto-granulator94 in the literature. A schematicof the fluid-bed rotor granulator is shown inFigure 8. The disk has variable size slit opening


Figure 8. Rotor disk granulator with tangentialspray system. Fg, gravitational force, Fc centrifugalforce, and Fv, vertical force.


between the bowl wall and rotating disk. Thespray nozzle is located at the lower plenum ofthe wall such that it is fully immersed in thespheronizing powder mass. The fluidization airenters through the slit openings while the binderfluid is being sprayed by atomized air nozzleslocated in the side walls in opposite direction. Thisgives rise to a tangential spray on the fluidizingparticles. It is interesting to note that the flow ofmaterials in the rotary system is like a ‘‘spiralwreath’’ or ‘‘rope-like’’ motion or helical doughnut-shaped pattern.95–97 A number of rotary granu-lators are commercially available. The distinctivefeatures of the equipments are summarized inTable 1.98 The combination of the rotation andthe typical air flow pattern provides specificproperties to the resultant coated material such

Table 1. Important Features of Rotor Granulators

FeatureRotor Granulator

(Glatt)Rotor-Pro

(Aerom

Control of drying air Disk height;pan speed

Chamber wapan speed

Spray location Tangential Tangential atop (angle

Powder application Tangential into bed Top-angledDie speed Variable VariableCharging Port in expansion

chamberPort in expa

chamberDischarging Port in product

chamberPort in prod

chamber


as higher spherical shape and density. However, itshould be noted that the principal drawback ofthis design is the high agitation in the equipmentthat limits its application to coating materialswhich are not too crumbly or friable in nature. Ithas been observed that wet granulation usingrotary processor is a good alternative to conven-tional fluid-bed granulation when cohesive pow-ders with poor flow properties or formulationswith low drug content are to be granulated by afluidizing air technique.99

Traditionally the spheronization methodinvolves four basic steps of granulation, extrusion,spheronization and drying of pellets. This extru-sion/spheronization technique has been describedas the most popular choice for producing pel-lets,100 and the method of choice in the prepara-tion of spherical particles.101 In contrast to this, arotor disk fluid-bed technology is a single stepclosed process in which the binder solution isadded at a fixed rate onto the powder bed in thefluid-bed rotor. The particles in motion areagglomerated and spheronized simultaneously.The inlet air then dries the pellets to the desiredlevel. The fluid-bed technique has been developedto involve the rotor module for several differentmanufacturing processes.102 Tangential sprayinghas been shown to be a good choice for producingspheroids that can be coated for controlled releasein the same rotor insert.103–105 This typical motionis due to three directional forces namely thevertical movement caused by the air flow ( Fv)above the slit area around the bowl periphery, thegravitational force ( Fg) as the material folds overto the central part and the centrifugal force ( Fc)caused by the rotation of the disk. While thecentrifugal force is a function of the platerotational speed, the vertical distance traversedby the particles in the tumbling mass depends on

cessoratic)

Spir-a-Flow(Freund)

CF-Granulator(Freund)

ll height, Plenum dampers anddisk height, pan speed

Pan speed

ndd)

Tangential andtop (vertical)

Tangential

— Top verticalVariable Variable

nsion Port in chamber Top loaded

uct Port in productchamber

Port in productchamber

09 DOI 10.1002/jp
s


gap air velocity and bulk volume of the powdermass. Eqs. (1) and (2) are the modifications of theFroude number equation as reported by Horsthuiset al.106 for rotational speed (V) and centrifugalforce ( Fc), respectively. The centrifugal force isdirectly proportional to the weight (W) of thematerial and square of the rotational speed andinversely related to the plate radius (R)

V ¼ pFc

R

W(30)

Fc ¼WV2

R(31)

There are three better known manufacturers ofrotary Processors namely GEA-Aeromatic, GlattAir Technique and Vector/Freund Corporation.107

The basic design of these units contain distinctivefeatures. The prototype equipment was initiallyfirst developed in the 1970s108 and progress inmodifications to the basic design resulted in therotor granulator (Glatt), roto-processor (Aero-matic), spir-a-flow (Freund) and centrifugal gran-ulator (Freund). In few equipments, drying maybe a rate limiting step in centrifugal granulatorsthat are not enclosed in a fluidized bed system.109

In such cases, the air velocity can be controlled bythe width of the gap between the rotating plateand chamber wall and the height of the rotatingplate may be adjusted in some models. Severalprocessing techniques such as powder layering,solution layering, and wet spheronization, as wellas coating can be exploited. Wet spheronizationin rotary processor consists of three stages viz.addition of liquid, tumbling of material, anddrying.110 Dense spheroids of narrow size dis-tributions can be prepared by rotary spheroniza-tion.111–113

Single and Double Chamber Systems

Two basic chamber designs namely the singlechamber and double chamber systems have beenemployed in rotary processors. In the singlechamber type, the drying and coating takes placewithin the same chamber processor. This limitsthe drying capacity of the processor leading toextended processing time. The rotary processordouble chamber design consists of an inner metalchamber which is housed inside a larger outerchamber with the rotating plate resides within theinner chamber. A perforated metal ring surroundsthe two chambers. Fluidizing air is introduced


into the outer chamber via the perforations on themetal ring. The single chamber type design ismanufactured by Glatt as Glatt Rotor Granulator(Glatt GMBH, Germany) and by Freund (FreundIndustrial Co. Ltd., Japan) as a Spir-a-flowgranulator. The double-chamber design waspatented and manufactured by Aeromatic-FielderAG (Aeromatic-Fielder AG, now Niro PharmaSystems, Switzerland).114 While patent USPatent 3,671,296 is for the rotor technologyequipment and coating of the granular material,subsequent patents (US 4,034,126 and US4,542,043) are for the coating of sphericalgranules. Fluid Bed Multi-ProcessorTM (GEAPharma systems) enables attachment of modulesto the central fluid bed for specific functions likeblending, granulating, drying, pelletizing, andcoating. The equipment is versatile in function.It has both options of spray dryer granulator andtop spray granulator systems.

Rotating Plate Design and Its Significance

In the rotary processor the rotating plate plays avery significant role in material movement thatrelies mainly on the forces set up by the rotatingplate to bring about liquid distribution and mixingduring the liquid addition stage in spherodizationprocess. Different plate modifications can beemployed depending on the process and use. Forexample, when the rotary processor is used forpowder layering or coating with core spheroids,rotating plates with smooth surfaces or comple-tely smooth plates instead of plates with pro-tuberances are employed since the base materialused (like nonpareil seeds or core spheroids) havegood inherent flow properties. Although thesmooth plate avoids material adhesion it doesnot supply sufficient shear for effective spheroni-zation.115 In conventional extrusion-spheroniza-tion the rotating plate surface consists of groovesthat aid break up of rod-shaped extrudates and toreshape the short rods into spheres.116 The typicalcross-hatch pattern (Fig. 9A), where groovesvertically intersect each other is the mostcommonly encountered plate design. Plates withgrooves that are arranged in a radial pattern(Fig. 9B) is another modification and it is foundthat frictional forces from a radial patternedrotating plate is more uniform over the rotatingpowder mass and energy transfer is alsogreater.117 In comparison to this, for rotaryprocessor the plate with protuberances on the


Figure 9. Different types of base plates in fluid-bed granulators: (A) Cross-hatchpattern, (B) Radial design, (C) Pyramid shaped studs, (D) Teardrop shaped studs,(E) Smooth plate with wide spaced baffles.


surface is additionally needed. Since the produc-tion of rotary processed spheroids does not involvean extrusion stage and there is no necessity forcutting up extrudates during spheronizationprocess, studs with a smooth but undulatingdesign are desirable. Pyramid shaped studs withround edges (Fig. 9C) have been used in spheroidproduction by rotary processing.118–121 However itis found that in case of symmetrical studs, moistmaterials have a tendency to be trapped in thespace between two adjacent studs. Hence toovercome this, teardrop-shaped studs (Fig. 9D)have been designed which provide the necessaryshear force with minimal material adhesionduring wet spheronization.122,123 The materialof construction for rotating plate can be ofstainless steel or polytetrafluoroethylene (PTFE).It is observed that the PTFE rotating plateproduces higher spheroid yields compared to thestainless steel rotating plate. One step closedrotor disk fluid-bed technology has been employedto develop spheronized microparticles of ibupro-fen.124 However, it should be noted that astainless steel rotating plate (Fig. 9E) permitsfor greater heat conduction and better drying ofthe mass compared to a PTFE rotating plate.Besides the rotating plate, an agitator blade mayadditionally be incorporated to a rotary processorto exploit the combined advantages of high shearmixing and fluidization techniques. This intro-duces a tumbling and compacting action to theconventional fluid-bed system and producesspheroids of higher densities preventing lump


formation.125 Several investigators have describedthe use of PTFE in high shear mixers for reduc-ing adhesion of moist material on granulatorwalls.126–131 PTFE is also widely used in lining theproduct chamber wall to reduce material adhesionduring wet spheronization by rotary proces-sing.132–137 Formulation factors and process vari-ables that influence fluidized granulation andspheronization have been documented.138–144

Moisture Content of Wet Mass

The most critical and influential variable forspheroid growth was the amount of liquid binderpresent for wet spheronization. Some studies havedemonstrated the importance of the amount ofmoistening liquid in controlling size, size dis-tribution, shape, friability, and other physicalcharacteristics of spheroids produced by rotaryprocessing. It is reported that the surface plasti-city enhanced deformation, assisting the roundingof spheroids. Microcrystalline cellulose (MCC) isthe most widely used excipient in pelletization.Among all types of MCC supplied, Avicel PH 101 isthe most commonly used grade.145–149 The speedof the rotating plate affects spheroid particlesize.150 Although studies showed that spheroidsize increased with an increase in rotating speed,contrary results are also reported.151 A possibleexplanation for these contradictory findings canbe attributed to differences in methods and/orequipment used in both cases.

09 DOI 10.1002/jps


HOT MELT GRANULATION

During the conventional solvent-based coatingprocess, a lot of energy is consumed for theevaporation of the large amount of solvent orwater used. Hot melt coating has been used as analternative method. The coating material ismelted by heating and sprayed on to the particleswhich then is solidified by stream of cold air.This is somewhat similar to the spray congealingtechnology using spray dryer. By virtue of thetechnique; the advantages are the processingtime is short, there is no particle shrinkage, nodrying step is required, low energy consumption,no solvent needed, that is, low cost, flexible andconsistent. However main drawbacks are the sizeand density of the final product, the bed depth andair velocity. Further, it is suitable mainly for fats,waxes and molten materials that are used inliquid coating, taste masking or altering drugrelease. This method is not suitable for thermo-labile actives in which case the conventional rotortechnique is to be followed. Recent studies haveshown, however, that a meltable binder can be analternative to a polymer solution in fluidized bedgranulation.152–157 Previous studies with aqueousbinder liquids in fluidized bed granulatorsreveal that larger binder droplet size158–162 andincreased viscosity of binder liquid163–165 resultin larger agglomerates. During the agglomerationprocess using water as binder, small agglomerates(nuclei) are formed followed by growth bycoalescence.166,167 There are series of paperspublished on melt granulation.168–172 Recentlycomelt system was developed in fluidized bedgranulation.173 Several studies have described theeffect of certain process variables on the meltgranulation of pharmaceutical type powders.174–178

It has been found that granules produced by fluid-bed granulation are more porous, less dense andmore compressible than granules from the highshear granulation process.179 In practice dis-solved or molten coating polymer is sprayed intoa bed of fluidized core material usually by meansof a pneumatic nozzle which may be submerged inor positioned above the bed.180–183

Electrostatic Fluid-Bed Coating

Another development in this field is the electro-static fluid-bed coating. Several researchers haveacknowledged the potential benefit of usingelectrostatic forces to improve deposition effi-


ciency. The first commercial version of automatedelectrostatic paint lines were developed withsignificant contributions in the 1970s. Later manymodels simulating electrostatic spray paintingbased on Lagrange’s approach were pro-posed.184,185 In the electrostatic fluidized bedpowder coating process, dry air is ionized bycharging media. In electrostatic deposition pro-cess charged materials are attracted to agrounded surface just like lightning seeks earth.Charging electrodes, fed by a high voltage supply(dc 0–100 kV) with a negative polarity onelectrodes is generally placed inside the bottompart of the bed so that the powder material wouldbe charged as the fluidizing air causes it to rise upin an electrically grounded column. The chargedparticles repel each other and rise from the base ofthe fluidizing bed chamber causing a cloud ofionized powder. The charged particles areattracted to the substrate, temporarily adheringto it before the curing process when a groundedwork-piece is dipped in the cloud. The coretechnology platform of QtrolTM (Phoqus)186 isderived from electrostatic deposition, the well-proven technology behind photocopying. Thistechnology enables solid dosage forms to be coatedin a controlled and precise manner to modify drugrelease characteristics. No solvent is employedand the process gives fine control over thethickness and location of a coating on the surfaceof the tablet. The substrate (tablet) is electricallygrounded so that when a high voltage is applied tothe coater the coating particles gets attracted tothe tablet and gets deposited onto its surface. Thethickness is controlled according to the potentialdifference between tablet and coater. The powderis fixed to tablet core by applying radiant heat.The concept of electrostatic coating has beenstudied by various research groups.187–192

Further research in this area of electrostaticcoating technique coupled with fluidized bedtechnology can be probed for further improve-ments in this area.

Supercritical Fluid (SCF) Fluid-Bed Coating

During particle coating it is observed that largedroplets in the bed lead to excessive size enlarge-ment of granules and sometimes bed defluidiza-tion, especially in case of fine particles.193 Therapid expansion of supercritical fluid solution(RESS) process has been used for particle coatinggranulation in fluidized beds.194,195 The studies



were conducted using rapid expansion of carbon-dioxide solution using silica as core particles. Theagglomeration tendency was eliminated due toabsence of liquid droplets in the process. Recentstudies have been done using supercritical flui-dized coating.196–199 Application of this technologyof SCF coupled to fluidized bed can be furtherexploited in pharmaceutical coatings.

GENERAL PROCESSING ISSUES

Agglomeration, granulation and coating arethe main applications of a fluid-bed technologyprocess.200–202 Various parameters influence thefinal product characteristics (Table 2). Since thisarticle is mainly focused on equipment design andprocessing aspects, the formulation parametersaffecting particular process have not beenaddressed. A multitude of possible problems arelikely to be encountered in a fluidized basedtechnology and a few are highlighted here. Wetquenching of fluidized bed due to liquid bridge

Table 2. Parameters to Be Considered during Use of Flui

General Equipment Factors

Position of the air distributionplate affects the airflow pattern

Positive and negative pressure operation

Placement of Nozzle height in coaterand granulator should be such that theatomized coating solution does not dry before

Annular base shape of the equipmentgives better fluidization

Granulation Process

Position of nozzle with respect to material heightis important suitably for better contact ofbinder with the powder to be granulated

Adjustment of spray rate and spray pressureof binder is important to avoid over wettingand agglomeration phenomena

The outlet air temperature and pressure dropacross exhaust filters are the indicatorsof efficiency of the process


formation between core particles leading toagglomeration is a common phenomenon.203–206

Premature droplet evaporation may likely occurbefore droplet adhesion onto the surface ofthe core particles.207,208 Several factors play rolein premature droplet evaporation including theevaporative capacity of the bed, the droplet traveldistance and velocity, the droplet impingementefficiency and the droplet adhesion probability.209

As many as twenty key process variables havebeen identified in fluid-bed coating.210 Anotherproblem is the fragmentation of friable coreparticles and the crumbling of the coating byattrition giving reduced process yields.211–213 Thehumidity of fluidization air is important. Theeffect of seasonal effects on inlet air humiditylevels on the fluid-bed granulation process hasbeen studied.214,215 Elevated granulation masstemperature is a result of higher versus lowerinlet air humidity since the heat capacity of humidair is greater than that of dry air as perpsychrometry and thermodynamic principles.216

Thus, one should take into consideration all thepossible process variables during optimizationphase to achieve best results.

dized Bed Technique

Process Factors

As a thumb rule, the rate of drying increasesas the inlet air temperature increases.However care must be taken withthermolabile molecules/materials

A low humidity in the inlet air is preferredsince it gives faster drying rate

As the air flow rate increases, the rate ofdrying increases but the cost of dryingalso increases. Thus optimum airlow rate is recommended

Coating Process

Placement of the nozzle should beproper to avoid spray drying of thecoating solution before reaching the cores

Optimum droplet size of the coatingsolution is recommended duringthe coating operation

Adjustment of spray rate and spray pressureis essential for optimum atomizationand efficient coating operation

09 DOI 10.1002/jps


CONCLUSION

Apart from formulation factors, the geometry ofequipment, aerodynamic principles and processengineering play a very noteworthy role inachieving optimum results in fluidized bedprocesses. Several options in processes and typesof equipment are available for lab scale to theproduction level. Depending upon the objective ofthe process, one can choose the required equip-ment. The innovative improvements of existingequipment designs for getting improved perfor-mance is an on-going process. With the basicunderstanding of electrostatic and SCF fluid-bedcoatings, further research avenues in this areamay prove to be a valuable tool and as analternative to existing technologies.

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09 DOI 10.1002/jps

fluidization technologies: aerodynamic principles and process engineering

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