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Recent Patents on Drug Delivery & Formulation 2008, 2, 209-230 20

1872-2113/08 $100.00+.00 2008 Bentham Science Publishers Ltd.

Innovations in Coating Technology

Sharareh S. Behzadi*, Stefan Toegel and Helmut Viernstein

Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna, Austria

Received: February 13, 2008; Accepted: July 1, 2008; Revised: September 1, 2008

Abstract: Despite representing one of the oldest pharmaceutical techniques, coating of dosage forms is still frequentlyused in pharmaceutical manufacturing. The aims of coating range from simply masking the taste or odour of drugs to the

sophisticated controlling of site and rate of drug release. The high expectations for different coating technologies have

required great efforts regarding the development of reproducible and controllable production processes.

Basically, improvements in coating methods have focused on particle movement, spraying systems, and air and energy

transport. Thereby, homogeneous distribution of coating material and increased drying efficiency should be accomplished

in order to achieve high end product quality. Moreover, given the claim of the FDA to design the end product quality

already during the manufacturing process (Quality by Design), the development of analytical methods for the analysis,

management and control of coating processes has attracted special attention during recent years.

The present review focuses on recent patents claiming improvements in pharmaceutical coating technology and intends to

first familiarize the reader with the available procedures and to subsequently explain the application of different analytical

tools. Aiming to structure this comprehensive field, coating technologies are primarily divided into pan and fluidized bed

coating methods. Regarding pan coating procedures, pans rotating around inclined, horizontal and vertical axes are

reviewed separately. On the other hand, fluidized bed technologies are subdivided into those involving fluidized andspouted beds. Then, continuous processing techniques and improvements in spraying systems are discussed in dedicated

chapters. Finally, currently used analytical methods for the understanding and management of coating processes are

reviewed in detail in the last section of the review.

Keywords: Coating technologies, pan coating, fluidized bed coating, continuous processing, process analytical technologies.

1. INTRODUCTION

Coating of pharmaceutical dosage forms has beenpracticed for many centuries. The first reports on this topicdate back to the 9th-11th century AD. Zakariya al-Razi (850-923) coated pills with the mucilage of Plantago psyllium,and Avicenna (980-1037) reported on the use of silver for

pill-coating in his famous book Al Qanun. The art ofcoating with honey, and later with sugar, was first reported atthe same time in France. At those times, masking theunpleasant taste and odour of bitter drugs represented themain purpose of pill-coating. The idea of coating with sugarwas to sweeten the bitter pill, whereas gold and silvercoatings were specially prepared for people of rank. Thecoating processes were initially conducted in copper pans,hanging from the ceiling on two chains over an open fire.The first hand-driven coating pan was described in 1840 anda patent for a spherical pan was granted in 1844 [1]. With theadoption of sugar coating from the confectionary industry,taste-masking remained the particular purpose of coatinguntil the mid 1950s. At this time, the industrial nature of the

coating process advanced through the use of ventilators.Initially, ambient air and then heated air were employed asenergy carriers [1]. This, together with the development ofpolymer-based coating excipients with the ability to formvery thin coating layers (the so-called film coating), allowedadvanced applications including:

*Address correspondence to this author at the Department of

Pharmaceutical Technology and Biopharmaceutics, University of Vienna,Althanstr. 14, A-1090, Vienna, Austria; Tel: +43 1 4277 55417;Fax: +43 1 4277 9554; E-mail: [email protected]

- Improving the ease of handling;

- Increasing the drugs safety by indicating drug identity;

- Increasing compliance by improving optical appearance;

- Increasing the drugs shelf-life by protecting it fromenvironmental influences (such as oxygen, humidity, light

etc.)- Controlling the rate of drug release (for example bysustained release coating);

- Controlling the site of drug release (for example by entericcoating);

During the last decades, the efficiency of coating technologies has been improved due to noticeable developments inthe fields of air and energy transport, material movement andspraying systems. Moreover, different methods have beendeveloped for the analysis, management and control ocoating processes.

This review summarizes those inventions disclosed in th

patent literature related to the recent developments in coatingtechnology, and intends to inform the reader about theimprovements in different types of equipments and processing levels. For accessing the full-text and claims of therespective patents, the reader is invited to use the patennumbers listed in the reference chapter for on-line searching.

2. COATING TECHNOLOGIES

In the following, the various types of coating equipmentare broadly classified into (1) pan coaters and (2) fluidizedbed coaters. Whereas pan coaters are further organized into


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210 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 Salar Behzadi et al

pans rotating around inclined, horizontal and vertical axes,improvements of fluidized bed coaters are divided intofluidized and spouted bed coaters. Recent advances incontinuous processing methods and spraying systems will bediscussed in a separate section afterwards.

2.1. Pan Coaters

Conventional coating pans are those originally used for

the production of candies. Over the years, the use of coatingpans also became common practice in the pharmaceuticalindustry for the coating of relatively large particles andtablets. Generally, pan coaters offer low mechanical stress tothe cores and provide the required motion of the core bedduring the coating process.

2.1.1. Pan Coaters Rotating on Inclined Axis

In conventional coating pans, the core bed is moved in acontainer which is rotating on an inclined axis. Due to theinclined adjustment of the axis, two basic motions aresuperimposed: (1) the tumbling motion on the horizontal axisand (2) the centrifugal motion on the vertical axis. Thus, theresulting motion in the pan is a combination of these two

motions. The coating liquid is fed through a spraying nozzlewhich, in conventional pans, is installed at the front of theopening. Cores get coated as they enter the spray zone priorto cascading down and merging into the bulk of the core bed.At a certain time, the cores re-enter the spray zone and thecoating and drying process repeats [1, 2].

In general, conventional pan coaters suffer from twodisadvantages: (1) Inefficient particle movement resulting inthe appearance of so-called dead zones that impairhomogeneous mixing of the core bed, and (2) inadequate airtransport causing insufficient drying of the core bed.

As pan coaters rotating on horizontal axes actuallyrepresent an improvement of conventional pans, and as

further improvements in both technologies are very similar,they will be discussed together in the following section.However, it should be kept in mind that in most casesimproving particle movement automatically results in theimprovement of the drying process.

2.1.2. Pan Coaters Rotating on Horizontal Axis

This type of pans was developed in order to increase theaverage contact area of the core bed with the drying air. Byrotating on a horizontal axis, a tumbling motion of the corebed inside the container was created, resulting in reduceddrying time and advanced efficiency of the process in rela-tion to the volume of the pan. Despite this basic impro-vement, both the particle flow and the drying efficiency of

the bed still demanded further refinement as explainedbelow.

Improvements in the Particle Movement

Mixing of the core bed is important for a uniform appli-cation of the coating material as well as for effective drying.The most basic approach to improve the core bed movementin pans rotating on inclined or horizontal axes was tointroduce baffles andblades in the pan. One of the first panswith a single baffle was invented by Keil in 1965 [3].

The first coating pan rotating on a horizontal axisequipped with tapered side walls and an integral bafflesystem was introduced by Pellegrini [4] and is well-knownas the Pellegrini pan Fig. (1). The side walls of this pan arshaped with a pronounced taper, which increases thefficiency of particle movement by forcing the cores into anadditional lateral movement. This results in a composite coremovement yielding improved exposure of the core to the

coating material.

Fig. (1). Pellegrini pan, adopted from reference [1].

The problem of using baffles and blades lies in theincreased risk of friction between the core material and thepans, potentially resulting in increased amounts of dusformed during the coating process. Hence, inventors havefocused on the implementation of perforated pans to improvthe air transport in the core bed and consequently to increasethe mixing and drying efficiency. Hostetler [5], for instancehas modified the peripheral wall with perforations andpositioned an air supplying inlet at the lower peripheral areaforming the so-calledside-vented pan Fig. (2). The shape othe pan, the perforations in the peripheral wall, and the side

positioned air supplying inlet were not only intended toincrease core movement and air transfer, but also to increasthe contact area of the cores with the coating material.

Fig. (2). Side-vented pan of Hostetler [5].

In order to reduce the occurrence of dead zones, Bohle[6] has provided perforated carriers inside the pan focontrolled movement of the cores. By using more than onepan and by connecting the pans with passages it also becam


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Innovations in Coating Technology Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 21

possible to operate the coating process continuously. Thisapproach was further refined by providing feeding anddischarging devices in the first and last pan, respectively [7]Fig. (3).

Fig. (3). Pan with perforated carriers of Bohle [7].

Improvements in Drying Efficiency

Generally, the energy required for evaporating themoisture from the coating layers is derived from the dryingair [1]. The duration of the coating process as well as thequality of the end product thus crucially depend on theefficiency of heat and mass transfer. Increasing the heat andmass transfer either directly (for example by increasingtemperature and rotation speed or implementation ofperforations) or indirectly by improving the drying air supplycan improve drying efficiency.

With the conventional drying method, the drying air isblown across the surface of the core bed. As only the surfaceof the core bed is exposed to the drying air, insufficientdrying of core materials and impaired spraying processesmight occur. Hence, different drying gadgets have beendeveloped, of which the two conventional ones are theimmersion tube and the immersion sword.

The immersion tube, developed by Strunck [8], is a benttube introducing the drying air directly into the coating bed.Together with the drying air, the coating material is sprayedfrom the immersed end of the tube directly into the bed Fig.(4). This method bears the advantage of reduced loss ofcoating material while having the disadvantage of creating

friction between the core material and the immersion tube.

The immersion sword Fig. (5) is divided into two ducts,one for supplying and one for exhausting the drying air. Inthis case, the coating material is usually sprayed from the toponto the surface of the core bed. The drying air is exhaustedbelow the surface of the core bed, which accelerates thedrawn of spraying liquid into the bed and avoids the excessloss of coating material [1].

Aiming to increase the drying efficiency, anotherdevelopment introduced perforations in the pan allowing the

Fig. (4). Coating pan with immersion tube adopted from referenc

[8].

Fig. (5). Coating pan with immersion sword adopted from referenc

[1].

passage of drying air. One variation is to supply the dryingair from above the core bed, concurrently with the sprayingdirection, and to exhaust it via the perforated pan. Theproblem in this case is that the drying air forces the coreagainst the perforated pan, unintentionally pressing the bedAnother variation is to supply the drying air through theperforations, and to exhaust it from above the core bedcounter-currently to the spray direction. Here, the disadvantage is that the spraying pattern is affected by the

counter-current air flow. One famous invention that avoidthese problems is the Accela Coata

, invented by Casey [9]

Here, the spraying nozzle is positioned within a drumconsisting of perforated walls. The drying air flows throughan air supplying inlet into the pan and fluidizes the core bedThe air outlet is closely placed at the upper part of the airinlet, drawing the core material along the perforated wallThis construction should provide improved mixing anddrying of the core material Fig. (6). Another approach focontrolling the direction of the drying air flow is the sidevented pan, which has already been mentioned in a previou


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Fig. (6). Accela Coata

[9].

section. In this invention, the air supplying inlet is installedin the lower peripheral area of the perforated wall andprevents the pressing of the core material to the inner wall ofthe drum [5] Fig. (2). Furthermore, Forster [10] covered

some parts of the perforated pan in order to reduce or evenavoid the flow of drying air through these parts. Then, thecoating liquid is applied to the core bed in these parts ofreduced air transfer. Afterwards, the coated cores are quicklytransferred to the perforated parts where the drying processstarts.

Another approach made the perforated drums suitable fortreatment of small dosage forms by avoiding the passage ofparticles into the perforations. For this purpose, throttledbaffles or scoops were provided to cover the perforated areas[11]. In another invention the wall of a side-vented pan wasprovided with wedge-wire sections consisting of triangularprofiles welded onto rods Fig. (7) [12]. In between thesetriangular profiles, peripheral gaps are placed. The width of

the gaps is adjustable with respect to the size of the particlesto be coated. Of note, this s tructure offers sufficient numbersof gaps in the wall in order to improve air transport in thebed.

Fig. (7). a) Pan with the wall provided of wedge-wired sections

b) A wedge-wired section [12].

In addition, the feeding and discharging of the pansduring the coating process were also improved. Trebbi hasprovided a pan with separate and independent feeding anddischarging openings to avoid the potential risk of conta-

mination between incoming and out-going products [13]. Tofacilitate the coating processes, Scipioni has invented a lidfor closing the coating pan which allows feeding anddischarging operations to be performed without having toremove drying and spraying devices usually attached to thelid [14].

2.1.3. Pan Coaters Rotating on Vertical Axis

The invention of dishes rotating on vertical axerepresents another approach towards the improvement of pancoating. This device was designed to overcome the problemof mechanical abrasion of cores encountered in horizontallyrotating pans with baffles or blades. Generally, in coaterthat rotate around vertical axes, the feed material to becoated is placed in a container which is moved by a drivingmotor. This causes the circulation of particles on the axis orotation. The centrifugal force first pushes the particleoutwards from the centre to the pan wall and then upwardfollowing the curve of the wall. Particles then drop downback into the middle of the container due to gravity. Usuallysuch equipments include a return device at the upper part othe wall which assists the feed material to roll back into the

container. This type of bed circulation intends to enable asmooth and gentle movement of particles. Furthermore, theshape of the container, the air transport and the direction osprayed coating material have been developed in order toachieve a more homogeneous distribution of coating materiaon the cores.

One of the first inventions with respect to verticallyrotating pans was introduced by Yoshiro et al. in 1971 [15]In this invention, the feed material is located in a pan placedinside a rotating device. A rotating stirrer is provided tomaintain a smooth movement of the particles close to thecylindrical wall of the pan. The spraying nozzle is installedin the upper part of the pan and the drying air can either flowupwards or downwards through the bed. Moreover, grooveor ridges on the dish can further assist the bed movement.

The conventional structure of vertically driven pans wafurther developed by different manufacturers. In order toimprove the drying process, Bretschneideret al. invented anequipment consisting of a rotating, conical and perforatedcontainer with a planar bottom [16] Fig. (8). For ease ohandling, the container was also removable. Cultivatorshaped return devices are installed at the top of the containeand the drying air is distributed through the perforated walinto the core bed, providing an intensive and homogeneoudrying of the feed material. Both speed and temperature othe drying air can be conditioned depending on the propertieof the feed material. Later, in order to enhance the particle

movement and to avoid the abrasion of feed material, thecultivator-shaped return devices were replaced by guidevanes [17] Fig. (9).

Modifications of the bottom and the air supplyingdevices were arranged by Httlin. He proposed a rotatingcontainer with a bottom consisting of several concentricrings [18] Fig. (10). The adjacent rings overlap each otheforming a series of concentric slits. The process air passesthrough the concentric slits and through a gap between thbottom and the container wall. The bottom and the containe


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Fig. (9). The vertical driving pan with guide vanes [17].

wall can be uncoupled, allowing the bottom and thecontainer to be driven at a independent rotary speed. At theupper part of the container, a conventional return device isinstalled, whereas the spraying nozzle is mounted between

the lower end of the return device and the bottom. Thedescribed set up aims at moving the particles in a lescompact manner, which allows more efficient drying.

In a later invention, the upper part of the wall (closely tothe return device) is equipped with at least one slit foairflow [19], providing an air bearing that prevented thefriction between the material and the return deviceFurthermore, the static bottom of the container is providedwith air slits in order to allow the drying air to flowtangentially through these slits towards the container wall. Inaddition to the drying effect, the resulting air bearing avoidsthe contact between feed material and slits.

In a subsequent invention, the concentric arrangement o

overlying rings is modified to provide a breaking-up zone[20]. This zone is formed by the collision of two air streams(1) one flowing from the concentric gaps near the centrtowards the container wall, and (2) the other flowing fromthe concentric gaps near the container wall towards thecentre. Consequently, the material is forced into a verticamovement along the breaking-up zone. After a certaindistance, however, the material drops down on both sides o

Fig. (8). The vertical driving pan with conical perforated container and cultivator-shaped return device [16].

Fig. (10). Pan coater rotating around a vertical axis of Httlin [18].


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the zone. The spraying nozzle is positioned directly in thebreaking-up zone, where the feed material is very intensivelyfluidized Fig. (11).

2.2. Fluidized Bed Technology

2.2.1. Fluidized Bed Equipment

Fluidized bed technology has been used in the phar-maceutical industry for a long time. With this type ofprocessing, the feed material is placed into a processingchamber and held in the fluidized state by a controlled air orgas current. Following the direction of the fluidizationair/gas flow, the main parts of a fluidized bed equipment canbe named as: air/gas inlet chamber, air/gas distribution base

plate, process chamber, spraying system and exhaustchamber [21] Fig. (12). In general, the air/gas inlet chamberrepresents the lowest part of a fluidized bed equipment.According to the requirements and the construction of the

whole device, this chamber is available in single or dividedmodification. In the case of a divided gas inlet chamberdifferent fluidization air flows can enter the equipmentThese flows can be conditioned, for example, with differentemperatures and flow rates which is of special importance inthe case of continuous processing [22, 23]. Between the gainlet chamber and the processing chamber, a distributionbase plate is installed which distributes the air/gas flowacross the whole cross-section of the processing chamberStatic or perforated distribution base plates are availableConventional rotating plates are commonly used incombination with tangential spray systems. In this case, thcircular base plate is not permeable, and the fluidizationair/gas enters the process chamber through a ring-shaped gap

between the process chamber wall and the rotating d isc. Theprocessing chamber itself can be cylindrical or conical [1, 821, 24]. The various spray systems employed in this system

Fig. (11). Cross section of the coating apparatus with breaking-up zone of Httlin [20].

Fig. (12). Main parts of the fluidized bed equipment with different processing methods.


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will be discussed in detail in a separate section of thisreview.

In fluidized bed technology, processing methods aremainly characterized by the spraying direction and thedesign principle of fluidization air/gas distribution into theprocessing chamber. Different processing methods are: topspray, bottom spray, wurster androtorsystems Fig. (12).These methods have been developed in order to permit

application of different processes such as granulation,pelletization, drying, coating and layering.

In the basic case of the top spray method, the spraynozzle is installed at the upper part of the process chamber,above the fluidized bed. The liquid is sprayed counter-currently onto the fluidized particles. Generally, this methodis more suitable for granulation. However, because of theuncontrolled fluidized bed, which does not guarantee optimaldistribution of coating liquid on the bed, the conventional topspray method is not suitable for preparing dosage forms withmodified release profiles.

In the case of the bottom spray method, the nozzle isinstalled at the bottom of the processing chamber and sprays

upwards, concurrently into the fluidized bed. Based on thisbottom spray method, the wurster method was introducedin 1959 by Wale Wurster. His construction involves a smallinner column (the so-called wurster), which is mountedabove the centre of the air d istribution base plate surroundingan upwards-directed nozzle. The perforations in the airdistribution base plate are larger in the centre, smallertowards the periphery, and larger again along the outermostcircle. This arrangement facilitates a strong air stream and anupwards-directed core movement inside the wurster and adrop of the cores outside the wurster. An elevated air streamnear the edge of the container prevents the cores from beingpressed to the container wall.

In the case of the rotor method, the particles are forcedinto a rotating movement either by a special design of the airdistribution base plate and the resulting air/gas flow or by arotating disc plate. In the case of the conventional rotormethod, the fluidizing air/gas enters the process chamberthrough a ring gap between the process chamber wall and arotating disc. This construction is responsible for the circularmovement of the feed material, while the coating liquid issprayed tangentially through the bed. As recent develop-ments in fluid bed technology have enabled the combinationof the rotational movement of a core bed with the bottomspray method, the rotor method could also be subcategorizedunder bottom spray processing.

Conventional rotor processing is the accepted method forpelletization and drug layering. For coating, however, boththe bottom spray processing including the wurster systemand the rotor processing are the methods of choice. Thewurster processing is particularly suitable for coating, meltcoating and drug layering processes. However, due to thedefined movement of particles in the process chamber andthe more homogeneous distribution of the spraying liquid ascompared to the top spray method, the utilization of thewurster method has also been reported for granulationprocesses [25]. It should be considered, however, that theconventional bottom and rotor methods are more advan-

tageous for coating of multiparticulate dosage forms, i.epellets and small cores. In contrast, the coating of largedosage forms, especially of tablets with sharp edges, involves the problem of core abrasion during the process. For thiapplication, both spouted bed and pan coaters appear moresuitable.

Improvements of the fluidized bed process have aimed totackle following problems:

- Influence of the fluidized bed on the spray pattern;

- Tendency of spray drying;

- Heterogeneity of the fluidized bed and of the sprayingliquid distribution on the bed;

In the following, each of these issues will be discussedseparately. However, it should be kept in mind that somemodifications have been invented to overcome more thanone problem at the same time.

Influence of the Fluidized Bed on the Spray Pattern

Due to the close distance between the circulating bed andthe spray nozzle, particularly in the bottom spray method

particles may enter the spray pattern before it has fullydeveloped. This results in uncontrolled droplet formation anddecreases the effectiveness of the system due to excessiveagglomeration and elevated processing time [26]. To avoidthese problems, different inventors have modified the designof the nozzle. Jones et al. [27] have provided a means foshielding the wurster spray-nozzle so that the particles arkept away from the sprayed coating liquid until the spraypattern has fully developed. This was achieved by surrounding the nozzle tip with an impermeable cylindrical shieldequipped with an upwards-directed air flow. This construction induced an annular and particle-free airflow around thnozzle body, allowing the spray pattern to fully develop intoa finely atomized mist before the particles can approach Fig

(13).

Fig. (13). Fluidized bed equipment with an impermeable cylindrica

shield for protection the spray pattern [27].

Almost 10 years later, Bender [28] modified the invention of Jones aiming to obtain a more uniform product. Inthis modification, the cylindrical shield was permeable inorder to permit smaller particles to enter the developingspray pattern and to agglomerate. The size of the openings


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was selected to limit the size of particles that could passthrough. This resulted in a narrower size distribution of theparticles to be coated. Subsequently, the homogeneous feedmaterial was exposed to the fully developed droplets ofcoating liquid.

In another invention, Jensen [29] used a diverter whichsupplied a radial airflow around the nozzle pushing away thematerial from the developing spray zone Fig. (14).

Fig. (14). Fluidized bed equipment with diverter for protection thespray pattern [29].

Tendency of Spray Drying

One drawback of the top spray method is the tendency ofthe sprayed coating fluid to dry before reaching the surfaceof the feed material. The position of the spray nozzle in themiddle of the fluidized bed and the low density of the spraypattern directed against the bed appear to be the mainreasons for this problem. In addition, inhomogeneousparticle movement in the process chamber and instability ofthe fluidizing pattern can also occur. To avoid theseproblems, Yoshinori et al. [30] developed a process chamber

Fig. (15) with a converging conical end and a nozzle that isinstalled at the converging part of the container wall andsprays laterally directly into the fluidized bed. The atomizingand the fluidizing air can also be conditioned.

Fig. (15). Top spray apparatus with a converging conical ending

[30].

Heterogeneity of Fluidized Bed and of Spraying LiquidDistribution on the Bed

In conventional fluid bed technology, and particularly inthe case of the top spray method, air flows uncontrolledthrough the perforated air distribution base plate and therebythrough the processing chamber. The uncontrolled air currencan result in heterogeneous, turbulent layers, and thereby in heterogeneous fluidized bed. This prevents uniformdistribution of the coating (or binding) liquid on the feedmaterial in coating (or granulation) processes. The dryingprocess can also be affected. The bottom spray methodequipped with the wurster system was the first approach toprovide controlled particle movement. However, the problemof the wurster system is the unpredictable particle flow in thearea between the air distribution base plate and the innecolumn, directly below the column. This can result in theaccumulation of particles in this area and consequently inpulsating flow patterns, agglomeration and clogging of thenozzle.

In order to overcome these problems, current efforts aimto produce controllable and homogeneous particle

movements, while selectively spraying into those parts of thebed with the highest fluidization [31]. For providing a morehomogeneous fluidized bed, the design of the inlet airchamber, the air distribution base plate or the proceschamber have been varied to create special air distributionand consequently a defined particle movement. For enhancement of the particle flow in the space between inner columnand base plate, Kim et al. [32] have modified the air inlechamber and the air distribution base plate in a fluidized bedequipment with wurster system. In this invention, the airdistribution base plate consists of an annular apertursurrounding the spray nozzle. Furthermore, the part of thebase plate directly below the inner column is designedwithout perforations. The air inlet chamber consists of an ai

guiding pipe, installed directly under the annular apertureThis air guiding pipe provides an accelerated swirling aiflow towards the annular aperture Fig. (16). This construction provides a fluidization air flow with high velocity

Fig. (16). Wurster system with annular aperture surrounding the

spray nozzle of Kim [32].


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through the inner column and acceleration of particlesthrough the gap between the air distribution base plate andinner column. Depending on the equipment and the batchsize, more than one spraying nozzle can be used forproviding enough amount of coating material on the core bedper time. Later, this construction has been further improvedby regulating the temperature of the swirling air flow passingthrough the annular aperture [33].

The same inventor [34] has improved a bottom sprayfluid bed equipment for coating of tablets. In this equipment,the wurster was removed to prevent the damaging of thetablets. Instead of perforations, the air distribution base plateconsists of ducts arranged around the spray nozzle.Moreover, the peripheral part of the air distribution baseplate is inclined towards the spray nozzle. This constructionresults in a controlled fluidization air flow, which guides thetablets into the spray zone.

To improve the particle flow through the gap between theair distribution base plate and the wurster, Jones et al. [35]used additional air flows independent of the fluidization airflow passing upwardly through the base plate. These

additional air flows blow from two apertures constructed vis--vis in the lowest part of the product chambers wall directlytowards the inner column Fig. (17).

Fig. (17). Wurster system with additional air flows of Jones [35].

Another example for changing the air distribution baseplate design, is the top spray fluidized bed equipment by Jan[36], introducing a pair of perforated removable housingspositioned vis--vis at the bottom of the processing chamber.

One part of the fluidization air flow passes through thesehousings and flows in a circumferential manner into theprocessing chamber. Together with the other part of thefluidization airflow passing upwards through the base plate,this additional air movement produces a swirling motionenhancing the particle movement in the chamber Fig. (18).

One early invention of Httlin was the Kugel Coater

[1].This type of fluidized bed equipment provided a bottomspray system within a spherical product chamber. Returndevices, which are commonly used in rotating pans, wereinstalled at the top of the product chamber to support the

Fig. (18). a) Perforated housing b) Fluidized bed apparatu

equipped with perforated housings [36].

homogeneous circulation of core bed. The air distribution

base plate consisted of concentric slits as previouslydescribed [17]. The width of the slits was adjustable, whichallowed control over the amount and velocity of the air flowThis construction aimed to ensure a homogeneous andcontrolled circulating particle movement. The problem othis construction, however, is the risk of friction between thcore bed and the return devices or the slits at the base plateIn contrast to the spherical Kugel Coater

, the lates

invention of Httlin [37] comprises a cylindrical processingchamber without return devices Fig. (19). The air distribution base plate consists of a concentric arrangement ooverlapping guiding plates. This arrangement of the guidingplates provides a radial airflow moving the bed radiallytowards the wall of the process chamber, then upwards along

the wall and then back to the centre of chamber. Thishomogenous circulation of the bed is maintained withoufriction between the core bed and the wall of the processingchamber. A multimedia nozzle is placed in the centre of theoverlapping guiding plates, providing a horizontal sprayingpattern directed parallel to the bottom of the chamber. Thicombination is designed to enhance both the fluidization othe bed and the distribution of the spraying liquid. For adetailed description of the multimedia nozzle please refer tosection 2.4.

2.2.2. Spouted Bed Coaters

Spouted beds have been developed as an effectivealternative to fluidized beds for handling coarse particle

over 2 mm diameter [38]. Following the direction of thespouting air/gas flow, the main parts of spouted bedequipment can be defined as air/gas inlet chamber, openingdevice, process chamber, spraying system and exhauschamber. The air/gas inlet chamber comprises the lower parof the apparatus and - like in the fluidized bed system - canbe implemented in single or divided form. Unlike thefluidized bed processes, the spouting air/gas does not entethe processing chamber through the air distribution baseplate, but through an opening device with relatively highvelocities, typically between 1 and 30 m/s Fig. (20). Thopening device can be constructed as a central orifice or a


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longitudinal slot at the bottom. The process chamber is

usually cylindrical with a conical base, in the centre of whichthe opening device is installed [39]. In general, the sprayingsystem and the exhaust chamber are similar to those offluidized bed systems.

The construction of the opening device and the shape ofthe process chamber play an essential role in the particlemovement and the particle velocity. In the following, thedifferent designs for the opening device are described.

Mrl et al. [40] have developed an opening deviceconsisting two gorge-formed plates mounted on a connectingelement Fig. (21). This construction provides two processchambers. In order to prevent both thermal damage of thefeed material and heat loss by wall cooling, the chamber

walls are constructed as double walls, which are arranged ata defined angle () and can be conditioned regarding theirtemperature. The connecting element is adjustable in itsheight and can therefore be used to change the opening-width (h) of the gorge-formed device and adjust the airflow.Furthermore, it is possible to adapt the slots to affect theairflow. The problem of this design is the accumulation ofdebris on the slots, which interferes with the airflow pattern.

Later, Mrl et al. [41] have modified the above-mentioned opening device by providing a cylinder in the

Fig. (21). Spouted bed equipment with gorge-formed plates oMoerl [40].

lower region of the process chamber between the two wallFig. (22). The cylinder rotates on its longitudinal axis and iequipped with an opening for the passage of the airflow intothe process chamber. By rotating the cylinder it is possible tochange the effective cross-section of the opening and toadjust the airflow.

Jacob et al. enhanced the spouted beds by passing thespouting air through a gap instead of a cylinder Fig. (23

Fig. (19). The combination of concentric arrangement of overlapping guiding plates with a multi-media nozzle [37].

Fig. (20). Main parts of a spouted bed equipment with different processing systems.


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[42]. The airflow spouts the bed in an axial direction into theprocess chamber. The significant increase in the cross-section of the process chamber towards the top results in asharp decrease of the fluidizing velocity and controlledairflow pattern. The distribution of coating liquid into thespouted bed is also improved by a special positioning of thespray nozzle. Thereby, the coating liquid is sprayedselectively and adjustably into the particle flow. Both topand bottom spray directions can be used. Further, in order tooptimize the material movement and residence time ofparticles in each fluidizing chamber, Jacob et al. have furtherdeveloped the spouted bed for continuous processing [23],which will be discussed in the following section.

In order to improve the spray pattern in the bottom sprayspouted bed, Debayeux et al. [43] have modified the air/gasinlet chamber Fig. (24). Here, the air/gas inlet chamberconsists of an upwardly converging conical part, which islinked to the process chamber by a cylindrical part of a

diameter (d) and a height of 0.5-0.66 d. The outlet of thespray nozzle is positioned in the cylindrical part of thair/gas inlet chamber directly below the connection to theprocess chamber. This positioning allows the airflow to forma particle-free pocket or pouch-like area above the nozzleThus, the spray pattern can fully develop before it comes incontact with the feed material.

2.2.3. Filter Systems

The exhausting chamber, which is located at the uppepart of the fluidized or spouted bed apparatus, is equippedwith a filter system. Filter systems commonly consist ofilter elements being responsible for removing dust oparticles from the outlet air. The filter elements are usuallymade of textile bags, stainless steel multilayer screen fabricsantistatic plastic sintered materials, or any other kind opleated or un-pleated filter material.

Fig. (22). Spouted bed equipment with rotating cylinder [41].

Fig. (23). The spouted bed of Jacob [42].


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There are two conventional methods for cleaning thefilter elements during the processing: (1) shaking systemsand (2) reverse gas jets (back purge). In both cases, theremoved dust falls back into the process chamber [21].

When utilizing filters with a shaking system, mechanicalforces are used to clean the filter sacks. During the cleaningof the filter, the process airflow is stopped by closing anexhaust valve. After a certain cleaning time the shakingstops, and the process airflow is restarted by opening theexhaust valve. With this construction, the processing air/gasflow has to be stopped regularly. This can affect the coatingprocess and consequently the properties of the end product.

In order to solve this problem, double-chamber shakingfilters were developed. Here, the exhaust chamber is dividedinto two separate shaking filters. During the cleaning of onefilter segment, the other part of the filter remains active andmaintains a continuous process airflow [21].

Double-chamber constructions have been designed alsofor back purge systems [44] Fig. (25). In this case, each filtercartridge is linked to a back-purge cleaning gas inlet whichin turn is connected to a valve. This construction enables theconsecutive cleaning of each cartridge while the othercartridges keep operating.

Feldmann has improved the back-purge system by theinstallation of rotating back-purge cleaning gas inlets [45]

providing more efficient cleaning of the filters. Furthermore,a guiding device is installed to prevent the process gas/airfrom entering into the openings of the back-purge cleaninggas inlet. This construction contributes to the continuousjetting of back-purge cleaning gas.

In order to avoid the presence of filter elements in theprocess chamber (which might affect the particle movement)and also to improve the cleaning of the filter system, acollar-shaped filter has been invented by Httlin [46]. Ofnote, the height of this filter system is less than its diameter

Fig. (25). Double-chamber back purge filter system [44].

which makes the filter system sit deep inside the exhauschamber. The filter surface consists of numerous removablesmall packets in a radial arrangement. These packets aremade of multi-layer metal, anti static plastic material otextile and are seperated by narrow gaps. This constructionprovides a large surface for passage of the process air/gathrough the filter. In case of clogging or damage of thepackets, they can be easily removed rather than changing thewhole system. In order to return the particles back to theprocess chamber, a back purge system is provided, whichconsists of a rotating cleaning air inlet rotating above theupper surface of the filter and blowing air consecutively intoeach packet Fig. (26).

2.3. Continuous Processing

During the last two decades, continuous processing hasbeen developed in order to overcome the disadvantages o

Fig. (24). Modification of air/gas inlet chamber for improvement of spray pattern [43].


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the batch concept, namely the low production rate and thescale up problem. To change a batch apparatus into acontinuous one, feeding and discharging devices must beadded. A feeding device consists of a reservoir for storingthe feed material. From this reservoir, the feed material isguided into the continuous processing apparatus by a feederproviding variable feed rates. For this purpose, screw feedersor controllable rotary valves can be used. Indeed, the

interplay between feeding rate and discharging rate definesthe flow rate of the continuous process and determines themean residence time of the particles [21, 31]. Different typesof feeding and discharging devices have been described indetail elsewhere [21].

In the development of continuous processing, the firstconcept was based on a mono-cell apparatus equipped withfeeding and discharging devices. This offered the possibilityto operate exactly as with a batch apparatus [31]. Thisconcept has been widely used in all coating technologies,including pan and fluidized bed coating. An example forsuch continuous pans rotating on horizontal axes is theinvention of Ferrero, with a discharging device for removingthe feed material at predetermined intervals during theprocess [47]. A recent invention in this field is the perforateddrum of OHara et al. [48]. Here, a drum rotating on thehorizontal axis is equipped with an adjustable feeding deviceproviding the drum with a controlled amount or volume offeed material per unit of time. The discharging deviceconsists of a weir plate of a defined structure, which allowsthe removal of a determined amount of coated feed material.The predetermined amount of feed material together withregular discharging enables the continuous processing.Moreover, this apparatus is equipped with an advancedcleaning system.

In case of the mono-cell continuous fluidized bed apparatus, particles reaching a pre-defined size are automaticallydischarged via the discharging pipe located at the centre othe process chamber. The air velocity within the dischargingpipe can be controlled to achieve the desired classification othe product, based on the mass of the end product [31] Fig(27).

Fig. (27). Monocell continuous fluidized bed [31].

Later, in order to provide the possibility of performingdifferent processes in one apparatus, multi-cell continuou

Fig. (26). Collar-shaped filter of Httlin [46].


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devices have been developed. Rmpler et al. [22] havedescribed a horizontal continuous fluidized bed apparatus inwhich the air/gas inlet chamber is divided. Due to thisconstruction different fluidizing airflows with differenttemperatures can enter the equipment. Since the air flow andthe air temperature can be conditioned, different processingsteps can be carried out in separate parts of the processingchamber. The feed material is conveyed to the apparatus

only by means of the fluidizing air [21, 22] Fig. (28).Another example of a multi-cell apparatus is the

invention of Liborius [49], which consists of several processunits connected to each other. Each process unit consists ofan air/gas inlet chamber, an air distribution base plate, aprocess chamber, a filter system and a spraying system.During the coating process, the feed material is conveyedpneumatically. Controlled recirculation of particles occurswithin each unit and a controlled spray is applied to the feedmaterial in order to produce homogeneous distribution ofcoating material on the bed.

One example of continuous spouted bed has already beenmentioned in the section 2.2.2. [23], Fig. (29). This apparatus

consists of at least two processing units, connected to eachother with an overflow channel. Each processing unit iequipped with an airflow device, an inlet wall and returnflow wall, an outlet filter and a spraying system. The inleand the return flow walls form a cone. The inlets of theopening device can be shaped into a gap, perforated sheets othrottled baffles, which set the amount of supplied fluidizingair. Due to a second air flow across the spouted air flow, the

feed material passes through the overflow channels betweenthe processing units. The overflow channels can also beformed as cross-sectional openings, arbitrary transporsystems, etc. The processing conditions in the individuaprocessing unit can be set according to the conditionrequired for the material treatment.

2.4. Spraying Systems

Most coating processes involve the addition of one ormore liquids to the system. In order to achieve good processconditions, liquids have to be processes into very smaldroplets using nozzles. The spraying nozzles used in coatingtechnology differ in their structure and in the spraying

Fig. (28). Horizontal continuous fluidized bed apparatus [21].

Fig. (29). The continuous spouted bed of Jacob [23].


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pattern they produce. Commonly, two basic types of spraynozzles are available: (1) the hydraulic or so-called one-media nozzle and (2) the pneumatic nozzle Fig. (30).Hydraulic or one-media nozzles are airless nozzles suppliedwith high-pressure pumps that expose the coating liquid toatomizing pressures (50-150 bar).

Using pneumatic nozzles, the coating liquid is acce-lerated to high speed by means of compressed air. For this

purpose, atomizing pressures of 0.5-6 bar are usuallyapplied. The conventional form of a pneumatic nozzle is theso-called 2-media nozzle, referring to liquid as the firstmedium and atomizing gas or air as the second. Generally, intwo-media nozzles the opening for the coating liquid issurrounded with an air gap, where the atomization gas/air isguided to the liquid opening tip. At the opening tip, therelatively slow flowing liquid comes in contact with therapid gas stream. The resulting shearing forces atomize theliquid stream and produce a very fine mist. One advantage ofpneumatic nozzles is the larger opening for the coatingliquid, in comparison to the opening of hydraulic nozzles. Inthe case of spraying suspensions, dispersions and fluids withhigh viscosity, this larger opening offers a reduced tendencyof clogging of the nozzle. In addition, both spray rate andfluid delivery rate are easier to control using pneumaticnozzles [1, 24]. Therefore, pneumatic nozzles are typicallyused in the chemical, pharmaceutical and food industries,especially when combined with fluidized bed devices.

Depending on the location of mixing the liquid and gas,pneumatic nozzles with external or internal mixing designscan be distinguished Fig. (30). Conventionally, the liquid togas contact takes place just in front of the opening tip. Thiskind of pneumatic nozzle design is called external mixing. Inthe case of internal mixing, the tip of the liquid opening isinside the gas cap. Liquid and gas are mixed prior to leavingthe nozzle.

The spray pattern affects the particle wetting and thelocal liquid distribution in the core bed, which consequently

influences coating properties such as porosity, surfaceroughness and density. Generally, there are 3 different spraypatterns: full cone, hollow cone and flat jet pattern [21] Fig(30). In fact, each pattern is suitable for a main sprayingpurpose. The hollow cone pattern is usually used fogranulation and wetting purposes, whereas the full cone andflat jet patterns are typically used in coating processes. Theflat jet spraying pattern aims to improve the micronization o

liquid droplets with a relatively low air flow and low airpressure [50].

As pneumatic nozzles with full cone or flat jet sprayingpatterns are in demand in the pharmaceutical industry, thisection will focus on this type of nozzles. In the followingimprovements in different types of nozzles will be discussedIn general, most inventions aimed to enhance the spraypattern, to prevent the clogging of the nozzles and tofacilitate in-process cleaning.

External Mixing Nozzles with Flat Jet Spraying Pattern

The conventional method for obtaining a flat jet sprayingpattern is using flat jet caps with two deflecting flanges oso-called horns. These horns are placed vertically to thelongitudinal nozzle axis. The horns are provided withopenings for airflows, which are responsible for forming defined jet pattern Fig. (31). The central channel for thcoating liquid is surrounded by a channel for atomizing airThe coating liquid is atomized in front of the opening tip dueto this atomizing air. At the same time, a defined jet patternforms due to the airflows guided towards their openings ineach horn and towards the atomized coating liquid.

In the conventional model, the angular shape of the hornand the relatively long distance between the atomizing aiopenings and the central liquid opening cause the depositionof coating material on the surface of the flat jet cap. Thispotentially impairs the coating quality. Thus, Gerstner [51

has invented an external mixing nozzle with a flat jet capproviding a planar deflecting surface without horns

Fig. (30). a) Schematic diagram of hydraulic and pneumatic nozzles, the external and internal mixing designs for pneumatic nozzles, b)

Three different spray patterns.


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Furthermore, transitional regions between the deflectingsurface and the lateral surfaces are rounded off in order toavoid edges. The atomizing air openings producing the flatjet spraying pattern are located at the deflecting surface,within a short distance next to the central opening Fig. (32).The rounded design of the cap without deflecting flanges andthe short distance between the flat jet air flow openings andthe central positioned liquid opening prevent the depositingof coating material on the deflecting surface (the so-calledbeard building). Referring to this characteristic, the describedcaps are marketed as ABC-Technique (Anti Bearding Caps).

Fig. (32). Spray nozzle with flat jet cap of Gerstner [51].

Internal Mixing Nozzles with Flat Jet Spraying Pattern

In order to produce a wide and flat jet pattern, and toimprove the micronization of the coating liquid when usinglow air flow, Harruch has invented a modified internal

mixing nozzle. While the construction of a flat jet cap withhorns is maintained, this invention introduced internal mixing of coating liquid with the atomizing air before leavingthe nozzle. The atomized fluid becomes a jet pattern afterleaving the nozzle due to the airflows guided through theopenings in the horns and towards the atomized coating fluid[52].

An example for the improvement of internal mixingnozzles with conical spraying pattern is the invention byGianfranco [53]. In this invention, the channels for sprayingliquid and atomizing air were formed into conical shape inorder to produce more homogeneously atomized dropletwith low speed. The channel for atomizing air consists otwo diverse parts. The converged-shaped first part is followed by the second part with a diverged-shaped construction

The spraying liquid channel is positioned inside the firsconverged-shaped part of the atomizing air channel. Theatomizing air accelerates at a substantially higher volume acompared to the spraying liquid and impinges the liquidThis results in acceleration and atomization of the sprayingliquid. Due to the diverged-shaped part before the openingtip, the atomized liquid leaves the opening with reducedspeed Fig. (33).

Multi-Media Nozzles

In order to provide fine and homogeneous droplets, athree-media spraying system has been developed by Httlin[54]. This spraying system consists of three concentricaflow channels running from the inflow along a longitudina

axis to the opening tip Fig. (34). The spraying liquid channeis both internally and externally surrounded by additionachannels for spraying and guiding atomising air. While thespraying air is responsible for atomizing the coating liquidthe guiding air is intended to facilitate the targeted sprayingof this liquid on the surface of feed material. In order toavoid the drying of the spraying liquid inside the nozzle awell as clogging of the nozzle, the guiding air (the so-calledMikroklima) can be conditioned with different temperatures for example. In the modified form of this inventionthe channels are directed outwards from the longitudinal axitowards their opening at an angle of 15-90 [55]. Thi

Fig. (31). Spray nozzle with conventional flat jet cap.


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structure results in the diverged distribution of atomisedcoating liquid, and is intended to achieve two aims: (1) toavoid the overlapping of produced droplets and consequentlyto prevent the formation of large drops, and (2) to obtain awide angled spray cone. Depending on the properties of theliquid to be sprayed, the size of the spraying liquid channel

can be regulated. Moreover, the walls enclosing this channelare rotatable in opposite directions around the nozzle axiswhich aims to prevent the clogging of the nozzle.

Prevention of the Clogging of Nozzles

As mentioned before, the larger liquid opening ofpneumatic nozzles decreases the tendency of clogging ascompared to hydraulic nozzles. Nevertheless, the clogging oftwo-media nozzles remains a serious problem in the case ofpneumatic nozzles, particularly during the process . In thegeneral design of the two-media nozzles, the coating liquidinsert is connected to the nozzle body with a curve of 90.This connection area is the favourite place for deposition ofcoating material and preferentially causes clogging of the

nozzle. In order to overcome this problem, Beckendorff [56]has designed an external two-media nozzle, avoiding thecurve of 90 by the connection of coating liquid insert andliquid channel in the nozzle body. In the modified nozzle byBeckendorff, the nozzle body holds a removable liquidinsert, which is connected to an axial liquid channel and issurrounded by the atomizing air channel. Luy et al. [57] havedesigned a removable two-media spraying nozzle and anenclosing body, particularly for using in fluidized bedequipments with a bottom spray system. The enclosing bodyconsists of a central recess for fixing the removable nozzle,which is mounted at the bottom of the fluidized bed device.

The nozzle, adjusted in the enclosing body, is pressed to thebottom of the fluidized bed device utilizing air pressure. Incase of clogging of the nozzle during the process, thistructure enables the in-process removal and cleaning of thnozzle. An axially adjustable cleaning needle present in themiddle of the nozzle is connected with an actuation

equipment for cleaning the nozzle during the process. Griebet al. [58] have developed a 2-media spray nozzle with aflexible cleaning cap, made of silicon or another elasticmaterial, which is arranged around the nozzle cap. A feed foatomizing the cleaning air is arranged between the nozzlebody and the cleaning cap. The atomized cleaning aiprovides continuous bulge and vibration of the cleaning capresulting in the removal of product deposition at the nozzleoutlet.

Depending on the aim of coating or the composition othe spraying liquid formulation, it is sometimes necessary tospray different media separately at the same time. For thipurpose, a nozzle was invented [59] with separate channel

and openings for passage of different liquids. The openingfor different liquids and the opening for atomizing air formconcentric circles. Schlick GmbH [60] has developed anozzle containing a detachable fluid channel in the case ospraying different liquids one after the other. In anotherinvention [61] from the same company, individual spraynozzles are interconnected to each other by adapters withrespective channel outlets. This invention is intended toprevent the problem of cleaning the nozzle during theprocess by using more than one spraying liquid and to enablethe use of different types of nozzles during one process.

Fig. (33). The internal mixing nozzle of Gianfranco [53].

Fig. (34). Multi-media nozzle [54].


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3. CURRENT & FUTURE DEVELOPMENTS

Independent of the type of coating technology used,advanced coating properties can only be achieved if themanufacturing process is fully understood and controlled.This understanding and controlling of the manufacturingprocesses is the aim of PAT (Process Analytical Tech-nology) a new FDA initiative. PAT is defined as a systemfor designing, analyzing, and controlling manufacturingthrough timely measurements (i.e., during processing) ofcritical quality and performance attributes of raw and in-process materials and processes with the goal of ensuringfinal product quality [62]. Therefore, the objective of thePAT framework is to design and develop processes that canconsistently ensure a predefined quality at the end of themanufacturing process. The methods employed to achievethis goal can be categorized as:

Multivariate data acquisition and analysis tools Modern process analyzers or process analytical

chemistry tools

Process and endpoint monitoring and control tools Continuous improvement and knowledge management

tools [62]

It is not the aim of this review to discuss all availabletools separately and in detail. Instead, modern analytical andmonitoring tools for coating processes, which are supportedby PAT will be discussed.

3.1. Analytical Methods for Process Understanding andControlling

In this section, different methods for analysis, design andcontrol of the coating processes are reviewed without goinginto to much detail about underlying mathematical opera-tions. For the interested reader, however, the relevant

literature will be presented in each section.

The commonly used methods for process analysis aredivided into probabilistic and numerical methods.

The phenomenological and Monte Carlo modellings arepart of the probabilistic methods, whereas the computationalfluid dynamics (CFD) simulations and the discrete elementmodelling (DEM) are numerical calculations. Turton [63]and Pandey et al. [2] reviewed these methods with emphasison their application for modelling coating mass uniformity.In the following, their applicability for process analysis andcontrolling will be summarized. The utilization of linear andnon-linear methods for process characterization and optimi-zation will also be described.

Phenomenological Modelling

With this type of modelling, the process under study isconsidered to consist of several events, whereas the finalprocess represents the sum of these events [2]. Differenttechniques have been used to investigate particle flowpattern, particle density and velocity, and circulation time inthe pan and fluidized bed coaters. Positron emission particletracking (PEPT) has been used to investigate the particlesflow pattern in a rotating drum [64] and in an interconnectedfluidized bed reactor. Using PEPT, the motion of a single

radioactively labelled tracer particle has been tracked withina bed of similar but unlabelled particles [65].

The circulation time, circulation time distribution and thenumber of passes of the cores during the coating process in awurster system have been investigated using magnetic tracetechnology. The impact of changes in design and processparameters on the movement of particles and the occurrencof dead zones has been studied using this technique [66, 67]

Particle density and velocity have been measured in horizontal rotating pan and subsequently in a vibratingfluidized bed using magnet resonance imaging (MRI) [6869].

Walker et al. used Raman spectroscopy in order toprovide 3D maps of the density and chemical structure oparticles in a fluidized bed equipment. The informationgained was further used for the analysis of air flow dynamic[70].

Dressler et al. have employed microwave sensor devicefor measurement, monitoring and controlling of the particlemovement in fluidized or spouted bed equipments during thspraying process for coating and granulation. For thi

purpose, microwave radiation was directed into the core bedand the radiation reflected by particles was measured [71].

Monte Carlo Modelling

The Monte Carlo method is a quantitative modellingprocedure for predicting outputs expected from theory andexperiment. It is performed by random sampling fromprobability distributions of parameters influence the processsuch as core bed temperature, rotation speed of drumphysical properties of coating material, etc. Following theassumption that a process consists of several events, theparameters affect these events in such a way that a probability distribution is obtained. The average of all outputs othese randomly sampled probability distributions will yieldaccurate estimates of the outputs of real processes [2].

Several investigators have used Monte Carlo modellingfor studying the effect of coating parameters includingcoating period, air velocity, mixing rate of the particles andspray pattern on the coating mass distribution. Particlmovement and spray dynamics in both the fluidized and pancoaters have also been simulated utilizing this method omodelling [72-74].

The determination of coating uniformity and weighuniformity of coated tablets during the pan coating procesusing the Monte Carlo method was patented by Choi [75]Improvements in the programming of this modelling werundertaken in order to make the method more suitable fosimulating high speed particle movements and to accelerateparallel processing [76, 77].

According to current expert opinion, however, a priorprediction is not possible using phenomenological andMonte Carlo modellings, and certain model parametershould first be measured experimentally [2, 63].

Discrete Element Modelling (DEM) and ComputationaFluid Dynamics Modelling (CFD)

Using DEM and CFD simulations, pre-adjustment omodel parameters is not necessary. The DEM and CFD are


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numerical simulation tools. These types of modellings arewidely used for the investigation of flow patterns and gas-solid interactions in fluidized and spouted beds [78-84].Generally, there are two types of calculation options, thetrajectory and the continuum media method. CDF modellingsimulates the solids and gas flow in a continuum mannerusing Navier-Stokes equations. In contrast, DEM is one ofthe trajectory models, in which particle-particle and particle-

gas interactions are simulated by tracking them individually.To describe the dynamics of both the gas and particle phase,continuum (Eulerian) and discrete (Lagrangian) types ofmodels are employed. DEMs describe the gas phase as acontinuum, whereas each of the individual particles is treatedas a discrete entity and traced individually utilizing theNewtonian equation of motion [85, 86]. Deen et al. [85]reviewed the different approaches of DEM, i.e. the hard-sphere and the soft-sphere systems, their applications in theinvestigation of flow patterns in fluidized beds, and thedifferent particle-particle and gas-particle interactions. DEMsimulations have been used by Limtrakul et al. [87] for theinvestigation of the mixing behaviour in a vibrated fluidizedbed equipment. The effect of particle type, amplitude and

frequency of vibration and air velocity on the flow pattern ofparticles has been studied. Wang and Rhodes [88] have usedthese types of modellings for the investigation of the particlemean residence time near the walls of a fluidized bed, aswell as for the study of distance between particles andcontainer wall and particle to particle contact frequency.

In order to make the CFD simulations suitable forprocess controlling, Colman and Townsen have improvedthis type of modelling for real-time simulations [89]. Aimingto decrease the overall processing time, Duggleby and Balltransferred the computationally complex CFD calculations toa dedicated coprocessor [90]. Dewhurst has provided a CFDmodelling software publically available via world wide web.By logging on to the server computer and using the clientsoftware, one can select the individual application amongdifferent categories of engineering applications which areoffered in a menu. By giving the requested data, the servercomputer models the specified problem, prepares the resultsin an output form and informs the customer per email [91].

Linear and Non-Linear Calculation Methods

The influence of process parameters and coatingformulation on the end product quality can be investigatedby using the design of experiments (DOE) with appro-priate statistical analysis and regression. This method isuseful for indicating the relative significance of a number ofindependent variables and their interactions responsible for

the obtained result. A disadvantage of this method is thedependency of DOEs on predetermined statistical signi-ficance levels, as less significant terms are not included inthe models [92-94]. Non-linear calculation methods such asArtificial Neural Networks (ANNs) offer an alternative toDOEs. ANNs are models of a totally different kind, in whichall available data are used for making the models moreaccurate. Therefore, they are able to predict response valuesfor optimization and validation purposes more precisely thanDOEs. ANNs consist of a set of mathematical methods andalgorithms designed to mimic the basic functions of thehuman brain, i.e. association, learning and generalization

[95]. Each processing unit of an ANN fulfills three functions: The input, transfer and output functions sum up thinputs that the processing unit receives, apply a transfefunction to the summed inputs and produce an outputrespectively. A number of different network-learning processes is available, amongst which the feed-forward backpropagation is the most widely used. Typically, this type onetwork uses processing units placed in three types of layers

input, hidden and output, which is also termed a multi-layeperceptron (MLP). Each unit within one layer is connected tounits in adjacent layers with an associated weight. It is theadjustment of these weights which is undertaken duringnetwork training, as network training involves iterativelychanging the weights between neurons until the output signamatches the target output within a desired error minimumFinally, a regression coefficient may be calculated based onthe observed product properties and network predictedvalues [96].

The DOEs and ANNs are particularly useful for processand formulation optimization but ignore the physics behindthe process. Different investigators have used them focharacterization and optimization purposes. Barletta et al[97] have investigated the influence of coating time, appliedvoltage and air flow rate on the coating properties in anelectrostatic fluidized bed utilizing both DOEs and ANNsand compared the accuracy of these two methods. SalaBehzadi et al. [98] have used ANNs for the validation of modified fluid bed equipment for granulation processesVaithiyalingam et al. and Salar Behzadi et al. have usedDOEs and ANNs for formulation development purposes [99100]. In order to avoid complex calculations for thedetermination of the thickness distribution of coating layersEickmeyeret al. combined a phenomenological model withartificial neural networks [101]. Using this combination, thspecified known parameters are directly supplied to thephenomenological model as fixed input parameters. Thoseparameters whose effects on the spraying results areunknown should be supplied to an ANN. After treatment bymeans of the network and investigation of the effect of theseparameters on the spraying results, they will add to thespecified parameters in the phenomenological model. Amethod for optimization of the artificial neural networks habeen patented by Schaffer et al. [102]. The patent representthe architecture of the neural networks by symbol strings. Aninitial population of networks is trained and evaluated. Thestrings representing the fittest networks are modifiedaccording to a genetic algorithm and the process is repeateduntil an optimized network is produced.

3.2. End Point Monitoring

The quality of a pharmaceutical end product should beensured during the manufacturing process. Monitoring thprocess end point is an important tool for manufacturing product with predefined quality. During the last decadesapplication of process measurement tools based on spectroscopic techniques, particularly near infrared (NIR) reflectance and Raman spectroscopy, have gained importance fothe monitoring of different steps of pharmaceutical processes. In general, their popularity is based on the versatilitythe minimal sample preparation and the non-destructivnature of these methods. Moreover, remote fiber optic probe


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have enabled the use of NIR and Raman spectroscopy for thein-line investigation of pharmaceutical manufacturing pro-cesses and the determination of the process end point.However, the influence of physical properties on spectra andthe need for calibration using a reference techniqueobviously represent the major drawbacks of this technique.

NIR spectroscopy has been the leading analytical methodfor pharmaceutical processes for many years. Several

investigators have used the NIR reflectance spectroscopy forat-line analysis of tablet film coating. For instance, changesin coating thickness were determined by evaluating changesin the NIR reflectance spectra of the tablet surface [103-105].

Positioning a defuse reflectance fiber-optic probe insidethe coating equipments enabled different investigators toanalyse the in-line of film coating processes using NIRspectroscopy. Andersson et al. have analyzed the coatingthickness of pellets by NIR spectrometry and by using amultivariate calibration method in a fluid bed equipment[106]. Perez-Ramoz et al. have monitored the pan coatingprocess of tablets. The thickness of the coating was

determined by monitoring the decrease of NIR absorptionbands characteristic of a component of the tablet core andmonitoring the increase of NIR bands characteristic of acomponent in the coating material. Quantitative calibrationof NIR spectra was developed for the tracking of the coatingthickness [107].

Several steps of a manufacturing process such as meltgranulation, tableting of granules and coating the tabletshave been analyzed at-line using Fourier transform (FT)-NIRand infrared imaging spectroscopy coupled to a microscopeand equipped with a focal plane array (FPA) detector. Theeffect of time and temperature on the quality of meltgranules, the effect of compact force on the quality of tabletsand the effect of coating time and formulation on the qualityof coated tablets have been investigated [108].

The use of Raman as process analytical method is quitelimited compared to the use of NIR. This is due to theexpensive Raman equipments on the one hand and thesensitivity of Raman to interfering background light scat-tering on the other hand. Nevertheless, given its versatilityand the continuous progress in its efficiency, Raman spectro-scopy is believed to develop into a powerful analyticalmethod complementing NIR. Examples of applications usingRaman are polymorph screening and (in-line) monitoring ofblending and coating processes [109-112].

Romero-Torres et al. have used Raman spectroscopywith multivariate calibration for the investigation of coatingthickness of tablets coated in a pan coater [113]. In anotherstudy, the same authors have evaluated different calibrationmethods for using Raman spectroscopy as an analytical toolfor the investigation of coatings comprising fluorescentingredients [114].

El Hagrasy et al. have used non-contact Raman fiberoptic probes for in-line monitoring of coating in a pan coater.The effect of the pan rotation speed on the acquired signalwas investigated. Moreover, a quantitative calibrationmethod was developed for the determination of coatingkinetics and end point [112].

As mentioned above, application of remote fiber opticprobes facilitates in-line process monitoring with IR oRaman spectroscopy. The first remote fiber optic probe forRaman spectroscopy was reported by Schwab and McCreery[115]. In simple terms, it consisted of 2 single optical fibersone for delivering the laser light to the sample (the so-calledexcitation fiber), and one for collecting the light scattered bythe sample and transmitting it to the detector (the so-called

collection fiber). The efficiency of exciting and collectingRaman photons from any individual point in the samplehowever, was poor. Therefore, several developments havebeen undertaken to improve the efficiency and increase theintensity of Raman signal. Examples are using multiplefibers instead of one collection fiber and changing theoverlap between the emission cone of the excitation fiber andthe collection cones of the collection fiber in order toincrease the collection efficiency [116]. Another improvement involved the coating of the interior surface of thesample chamber in order to prevent the reaching of interfering light to the collection fiber. This coating comprisedadhesive and light-absorbing particles such as carbon blackMoreover, Raman spectrum was measured using two

different pressures. The first measurement was used as blancThe design of the probe prevented the exciting light fromentering the collection fiber and interfering with the Ramansignal [117]. Improvements in the design of excitation andcollection fibers have further been undertaken in order toincrease light coupling efficiency and consequentlyenhancement of signal intensity [118]. Using additionaoptical elements enabled the collection of spectra from largeareas of the sample under study (spot sizes of 1 mm ogreater) compared to conventional optical elements whichutilize spot sizes of 2-60 m. The larger spot size facilitatethe collection of statistically useful data from inhomogeneous samples, which is a benefit for in-line processmonitoring [119].

Improvements in probe housing have also beenundertaken to facilitate the cleaning of the optical windowduring the processing and facilitate the in-line monitoring[120, 121].

4. CONCLUSION

In recent decades, coating of pharmaceutical dosageforms has been subject of remarkable developmental effortaiming to ensure and enhance end product quality. Improvements regarding particle movement, heat and energytransfer, film distribution, drying efficiency and continuouprocessing have contributed to significantly develop thitechnology.

However, evaluation and success of further constructional improvements in coating methods appear to depend onaccurate analytical tools and advanced methods for processmodelling and control. In this regard, achieving optimamanufacturing efficiency and high end product quality stilremains a key challenge for future research efforts. Given threcent claims of the FDA to pursue regulation of end producquality during the manufacturing process (Quality byDesign), future developments should strengthen the improvement of more powerful analytical, monitoring andmanagement tools in order to ensure the control of aldecisive parameters.


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