DDF 2 3 Behzadi

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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 frequently used 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 and spouted 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 been practiced for many centuries. The first reports on this topic date back to the 9th-11th century AD. Zakariya al-Razi (850923) 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 of coating with honey, and later with sugar, was first reported at the same time in France. At those times, masking the unpleasant taste and odour of bitter drugs represented the main purpose of pill-coating. The idea of coating with sugar was to sweeten the bitter pill, whereas gold and silver coatings were specially prepared for people of rank. The coating 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 and a patent for a spherical pan was granted in 1844 [1]. With the adoption of sugar coating from the confectionary industry, taste-masking remained the particular purpose of coating until 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 as energy carriers [1]. This, together with the development of polymer-based coating excipients with the ability to form very thin coating layers (the so-called film coating), allowed advanced 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: sharareh.salar-behzadi@univie.ac.at 1872-2113/08 $100.00+.00
- 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 from environmental influences (such as oxygen, humidity, light, etc.) - Controlling the rate of drug release (for example by sustained release coating); - Controlling the site of drug release (for example by enteric coating); During the last decades, the efficiency of coating technologies has been improved due to noticeable developments in the fields of air and energy transport, material movement and spraying systems. Moreover, different methods have been developed for the analysis, management and control of coating processes. This review summarizes those inventions disclosed in the patent literature related to the recent developments in coating technology, and intends to inform the reader about the improvements in different types of equipments and processing levels. For accessing the full-text and claims of the respective patents, the reader is invited to use the patent numbers listed in the reference chapter for on-line searching. 2. COATING TECHNOLOGIES In the following, the various types of coating equipments are broadly classified into (1) pan coaters and (2) fluidized bed coaters. Whereas pan coaters are further organized into
2008 Bentham Science Publishers Ltd.
210 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3
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pans rotating around inclined, horizontal and vertical axes, improvements of fluidized bed coaters are divided into fluidized and spouted bed coaters. Recent advances in continuous processing methods and spraying systems will be discussed 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 coating pans also became common practice in the pharmaceutical industry for the coating of relatively large particles and tablets. Generally, pan coaters offer low mechanical stress to the cores and provide the required motion of the core bed during the coating process. 2.1.1. Pan Coaters Rotating on Inclined Axis In conventional coating pans, the core bed is moved in a container which is rotating on an inclined axis. Due to the inclined adjustment of the axis, two basic motions are superimposed: (1) the tumbling motion on the horizontal axis and (2) the centrifugal motion on the vertical axis. Thus, the resulting motion in the pan is a combination of these two motions. The coating liquid is fed through a spraying nozzle which, in conventional pans, is installed at the front of the opening. Cores get coated as they enter the spray zone prior to cascading down and merging into the bulk of the core bed. At a certain time, the cores re-enter the spray zone and the coating and drying process repeats [1, 2]. In general, conventional pan coaters suffer from two disadvantages: (1) Inefficient particle movement resulting in the appearance of so-called dead zones that impair homogeneous mixing of the core bed, and (2) inadequate air transport causing insufficient drying of the core bed. As pan coaters rotating on horizontal axes actually represent 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 cases improving particle movement automatically results in the improvement of the drying process. 2.1.2. Pan Coaters Rotating on Horizontal Axis This type of pans was developed in order to increase the average contact area of the core bed with the drying air. By rotating on a horizontal axis, a tumbling motion of the core bed inside the container was created, resulting in reduced drying time and advanced efficiency of the process in relation to the volume of the pan. Despite this basic improvement, both the particle flow and the drying efficiency of the bed still demanded further refinement as explained below. Improvements in the Particle Movement Mixing of the core bed is important for a uniform application of the coating material as well as for effective drying. The most basic approach to improve the core bed movement in pans rotating on inclined or horizontal axes was to introduce baffles and blades in the pan. One of the first pans with a single baffle was invented by Keil in 1965 [3].
The first coating pan rotating on a horizontal axis equipped with tapered side walls and an integral baffle system was introduced by Pellegrini [4] and is well-known as the Pellegrini pan Fig. (1). The side walls of this pan are shaped with a pronounced taper, which increases the efficiency of particle movement by forcing the cores into an additional lateral movement. This results in a composite core movement 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 the increased risk of friction between the core material and the pans, potentially resulting in increased amounts of dust formed during the coating process. Hence, inventors have focused on the implementation of perforated pans to improve the air transport in the core bed and consequently to increase the mixing and drying efficiency. Hostetler [5], for instance, has modified the peripheral wall with perforations and positioned an air supplying inlet at the lower peripheral area, forming the so-called side-vented pan Fig. (2). The shape of the pan, the perforations in the peripheral wall, and the sidepositioned air supplying inlet were not only intended to increase core movement and air transfer, but also to increase the 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 for controlled movement of the cores. By using more than one pan and by connecting the pans with passages it also became
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possible to operate the coating process continuously. This approach was further refined by providing feeding and discharging devices in the first and last pan, respectively [7] Fig. (3).
Fig. (4). Coating pan with immersion tube adopted from reference [8].
Fig. (3). Pan with perforated carriers of Bohle [7].
Improvements in Drying Efficiency Generally, the energy required for evaporating the moisture from the coating layers is derived from the drying air [1]. The duration of the coating process as well as the quality of the end product thus crucially depend on the efficiency of heat and mass transfer. Increasing the heat and mass transfer either directly (for example by increasing temperature and rotation speed or implementation of perforations) or indirectly by improving the drying air supply can improve drying efficiency. With the conventional drying method, the drying air is blown across the surface of the core bed. As only the surface of the core bed is exposed to the drying air, insufficient drying of core materials and impaired spraying processes might occur. Hence, different drying gadgets have been developed, of which the two conventional ones are the immersion tube and the immersion sword . The immersion tube, developed by Strunck [8], is a bent tube introducing the drying air directly into the coating bed. Together with the drying air, the coating material is sprayed from the immersed end of the tube directly into the bed Fig. (4). This method bears the advantage of reduced loss of coating 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. In this case, the coating material is usually sprayed from the top onto the surface of the core bed. The drying air is exhausted below the surface of the core bed, which accelerates the drawn of spraying liquid into the bed and avoids the excess loss of coating material [1]. Aiming to increase the drying efficiency, another development introduced perforations in the pan allowing the
Fig. (5). Coating pan with immersion sword adopted from reference [1].
passage of drying air. One variation is to supply the drying air from above the core bed, concurrently with the spraying direction, and to exhaust it via the perforated pan. The problem in this case is that the drying air forces the cores against the perforated pan, unintentionally pressing the bed. Another variation is to supply the drying air through the perforations, and to exhaust it from above the core bed counter-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 avoids these problems is the Accela Coata, invented by Casey [9]. Here, the spraying nozzle is positioned within a drum consisting of perforated walls. The drying air flows through an air supplying inlet into the pan and fluidizes the core bed. The air outlet is closely placed at the upper part of the air inlet, drawing the core material along the perforated wall. This construction should provide improved mixing and drying of the core material Fig. (6). Another approach for controlling the direction of the drying air flow is the sidevented pan, which has already been mentioned in a previous
mination between incoming and out-going products [13]. To facilitate the coating processes, Scipioni has invented a lid for closing the coating pan which allows feeding and discharging operations to be performed without having to remove drying and spraying devices usually attached to the lid [14]. 2.1.3. Pan Coaters Rotating on Vertical Axis The invention of dishes rotating on vertical axes represents another approach towards the improvement of pan coating. This device was designed to overcome the problem of mechanical abrasion of cores encountered in horizontally rotating pans with baffles or blades. Generally, in coaters that rotate around vertical axes, the feed material to be coated is placed in a container which is moved by a driving motor. This causes the circulation of particles on the axis of rotation. The centrifugal force first pushes the particles outwards from the centre to the pan wall and then upwards following the curve of the wall. Particles then drop down back into the middle of the container due to gravity. Usually, such equipments include a return device at the upper part of the wall which assists the feed material to roll back into the container. This type of bed circulation intends to enable a smooth and gentle movement of particles. Furthermore, the shape of the container, the air transport and the direction of sprayed coating material have been developed in order to achieve a more homogeneous distribution of coating material on the cores. One of the first inventions with respect to vertically rotating pans was introduced by Yoshiro et al. in 1971 [15]. In this invention, the feed material is located in a pan placed inside a rotating device. A rotating stirrer is provided to maintain a smooth movement of the particles close to the cylindrical wall of the pan. The spraying nozzle is installed in the upper part of the pan and the drying air can either flow upwards or downwards through the bed. Moreover, grooves or ridges on the dish can further assist the bed movement. The conventional structure of vertically driven pans was further developed by different manufacturers. In order to improve the drying process, Bretschneider et al. invented an equipment consisting of a rotating, conical and perforated container with a planar bottom [16] Fig. (8). For ease of handling, the container was also removable. Cultivatorshaped return devices are installed at the top of the container and the drying air is distributed through the perforated wall into the core bed, providing an intensive and homogeneous drying of the feed material. Both speed and temperature of the drying air can be conditioned depending on the properties of the feed material. Later, in order to enhance the particle movement and to avoid the abrasion of feed material, the cultivator-shaped return devices were replaced by guide vanes [17] Fig. (9). Modifications of the bottom and the air supplying devices were arranged by Httlin. He proposed a rotating container with a bottom consisting of several concentric rings [18] Fig. (10). The adjacent rings overlap each other forming a series of concentric slits. The process air passes through the concentric slits and through a gap between the bottom and the container wall. The bottom and the container
Fig. (6). Accela Coata [9].
section. In this invention, the air supplying inlet is installed in the lower peripheral area of the perforated wall and prevents the pressing of the core material to the inner wall of the drum [5] Fig. (2). Furthermore, Forster [10] covered some parts of the perforated pan in order to reduce or even avoid the flow of drying air through these parts. Then, the coating liquid is applied to the core bed in these parts of reduced air transfer. Afterwards, the coated cores are quickly transferred to the perforated parts where the drying process starts. Another approach made the perforated drums suitable for treatment of small dosage forms by avoiding the passage of particles into the perforations. For this purpose, throttled baffles or scoops were provided to cover the perforated areas [11]. In another invention the wall of a side-vented pan was provided with wedge-wire sections consisting of triangular profiles welded onto rods Fig. (7) [12]. In between these triangular profiles, peripheral gaps are placed. The width of the gaps is adjustable with respect to the size of the particles to be coated. Of note, this structure offers sufficient numbers of gaps in the wall in order to improve air transport in the bed.
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 pans during the coating process were also improved. Trebbi has provided a pan with separate and independent feeding and discharging openings to avoid the potential risk of conta-
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Fig. (8). The vertical driving pan with conical perforated container and cultivator-shaped return device [16].
the lower end of the return device and the bottom. The described set up aims at moving the particles in a less compact manner, which allows more efficient drying. In a later invention, the upper part of the wall (closely to the return device) is equipped with at least one slit for airflow [19], providing an air bearing that prevented the friction between the material and the return device. Furthermore, the static bottom of the container is provided with air slits in order to allow the drying air to flow tangentially through these slits towards the container wall. In addition to the drying effect, the resulting air bearing avoids the contact between feed material and slits. In a subsequent invention, the concentric arrangement of 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 centre towards the container wall, and (2) the other flowing from the concentric gaps near the container wall towards the centre. Consequently, the material is forced into a vertical movement along the breaking-up zone. After a certain distance, however, the material drops down on both sides of
Fig. (9). The vertical driving pan with guide vanes [17].
wall can be uncoupled, allowing the bottom and the container to be driven at a independent rotary speed. At the upper part of the container, a conventional return device is installed, whereas the spraying nozzle is mounted between
Fig. (10). Pan coater rotating around a vertical axis of Httlin [18].
Fig. (11). Cross section of the coating apparatus with breaking-up zone of Httlin [20].
the zone. The spraying nozzle is positioned directly in the breaking-up zone, where the feed material is very intensively fluidized Fig. (11). 2.2. Fluidized Bed Technology 2.2.1. Fluidized Bed Equipment Fluidized bed technology has been used in the pharmaceutical industry for a long time. With this type of processing, the feed material is placed into a processing chamber and held in the fluidized state by a controlled air or gas current. Following the direction of the fluidization air/gas flow, the main parts of a fluidized bed equipment can be named as: air/gas inlet chamber, air/gas distribution base plate, process chamber, spraying system and exhaust chamber [21] Fig. (12). In general, the air/gas inlet chamber represents 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 divided modification. In the case of a divided gas inlet chamber, different fluidization air flows can enter the equipment. These flows can be conditioned, for example, with different temperatures and flow rates which is of special importance in the case of continuous processing [22, 23]. Between the gas inlet chamber and the processing chamber, a distribution base plate is installed which distributes the air/gas flow across the whole cross-section of the processing chamber. Static or perforated distribution base plates are available. Conventional rotating plates are commonly used in combination with tangential spray systems. In this case, the circular base plate is not permeable, and the fluidization air/gas enters the process chamber through a ring-shaped gap between the process chamber wall and the rotating disc. The processing chamber itself can be cylindrical or conical [1, 8, 21, 24]. The various spray systems employed in this system
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 this review. In fluidized bed technology, processing methods are mainly characterized by the spraying direction and the design principle of fluidization air/gas distribution into the processing chamber. Different processing methods are: top spray, bottom spray, wurster and rotor systems 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 spray nozzle is installed at the upper part of the process chamber, above the fluidized bed. The liquid is sprayed countercurrently onto the fluidized particles. Generally, this method is more suitable for granulation. However, because of the uncontrolled fluidized bed, which does not guarantee optimal distribution of coating liquid on the bed, the conventional top spray method is not suitable for preparing dosage forms with modified release profiles. In the case of the bottom spray method, the nozzle is installed at the bottom of the processing chamber and sprays upwards, concurrently into the fluidized bed. Based on this bottom spray method, the wurster method was introduced in 1959 by Wale Wurster. His construction involves a small inner column (the so-called wurster), which is mounted above the centre of the air distribution base plate surrounding an upwards-directed nozzle. The perforations in the air distribution base plate are larger in the centre, smaller towards the periphery, and larger again along the outermost circle. This arrangement facilitates a strong air stream and an upwards-directed core movement inside the wurster and a drop of the cores outside the wurster. An elevated air stream near the edge of the container prevents the cores from being pressed to the container wall. In the case of the rotor method, the particles are forced into a rotating movement either by a special design of the air distribution base plate and the resulting air/gas flow or by a rotating disc plate. In the case of the conventional rotor method, the fluidizing air/gas enters the process chamber through a ring gap between the process chamber wall and a rotating disc. This construction is responsible for the circular movement of the feed material, while the coating liquid is sprayed tangentially through the bed. As recent developments in fluid bed technology have enabled the combination of the rotational movement of a core bed with the bottom spray method, the rotor method could also be subcategorized under bottom spray processing. Conventional rotor processing is the accepted method for pelletization and drug layering. For coating, however, both the bottom spray processing including the wurster system and the rotor processing are the methods of choice. The wurster processing is particularly suitable for coating, melt coating and drug layering processes. However, due to the defined movement of particles in the process chamber and the more homogeneous distribution of the spraying liquid as compared to the top spray method, the utilization of the wurster method has also been reported for granulation processes [25]. It should be considered, however, that the conventional bottom and rotor methods are more advan-
tageous for coating of multiparticulate dosage forms, i.e. pellets and small cores. In contrast, the coating of larger dosage forms, especially of tablets with sharp edges, involves the problem of core abrasion during the process. For this application, both spouted bed and pan coaters appear more suitable. Improvements of the fluidized bed process have aimed to tackle following problems: - Influence of the fluidized bed on the spray pattern; - Tendency of spray drying; - Heterogeneity of the fluidized bed and of the spraying liquid distribution on the bed; In the following, each of these issues will be discussed separately. However, it should be kept in mind that some modifications have been invented to overcome more than one problem at the same time. Influence of the Fluidized Bed on the Spray Pattern Due to the close distance between the circulating bed and the spray nozzle, particularly in the bottom spray method, particles may enter the spray pattern before it has fully developed. This results in uncontrolled droplet formation and decreases the effectiveness of the system due to excessive agglomeration and elevated processing time [26]. To avoid these problems, different inventors have modified the design of the nozzle. Jones et al. [27] have provided a means for shielding the wurster spray-nozzle so that the particles are kept away from the sprayed coating liquid until the spray pattern has fully developed. This was achieved by surrounding the nozzle tip with an impermeable cylindrical shield equipped with an upwards-directed air flow. This construction induced an annular and particle-free airflow around the nozzle body, allowing the spray pattern to fully develop into a finely atomized mist before the particles can approach Fig. (13).
Fig. (13). Fluidized bed equipment with an impermeable cylindrical 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. In this modification, the cylindrical shield was permeable in order to permit smaller particles to enter the developing spray pattern and to agglomerate. The size of the openings
was selected to limit the size of particles that could pass through. This resulted in a narrower size distribution of the particles to be coated. Subsequently, the homogeneous feed material was exposed to the fully developed droplets of coating liquid. In another invention, Jensen [29] used a diverter which supplied a radial airflow around the nozzle pushing away the material from the developing spray zone Fig. (14).
Heterogeneity of Fluidized Bed and of Spraying Liquid Distribution on the Bed In conventional fluid bed technology, and particularly in the case of the top spray method, air flows uncontrolled through the perforated air distribution base plate and thereby through the processing chamber. The uncontrolled air current can result in heterogeneous, turbulent layers, and thereby in a heterogeneous fluidized bed. This prevents uniform distribution of the coating (or binding) liquid on the feed material in coating (or granulation) processes. The drying process can also be affected. The bottom spray method equipped with the wurster system was the first approach to provide controlled particle movement. However, the problem of the wurster system is the unpredictable particle flow in the area between the air distribution base plate and the inner column, directly below the column. This can result in the accumulation of particles in this area and consequently in pulsating flow patterns, agglomeration and clogging of the nozzle. In order to overcome these problems, current efforts aim to produce controllable and homogeneous particle movements, while selectively spraying into those parts of the bed with the highest fluidization [31]. For providing a more homogeneous fluidized bed, the design of the inlet air chamber, the air distribution base plate or the process chamber have been varied to create special air distribution and consequently a defined particle movement. For enhancement of the particle flow in the space between inner column and base plate, Kim et al. [32] have modified the air inlet chamber and the air distribution base plate in a fluidized bed equipment with wurster system. In this invention, the air distribution base plate consists of an annular aperture surrounding the spray nozzle. Furthermore, the part of the base plate directly below the inner column is designed without perforations. The air inlet chamber consists of an air guiding pipe, installed directly under the annular aperture. This air guiding pipe provides an accelerated swirling air flow towards the annular aperture Fig. (16). This construction provides a fluidization air flow with high velocity
Fig. (14). Fluidized bed equipment with diverter for protection the spray pattern [29].
Tendency of Spray Drying One drawback of the top spray method is the tendency of the sprayed coating fluid to dry before reaching the surface of the feed material. The position of the spray nozzle in the middle of the fluidized bed and the low density of the spray pattern directed against the bed appear to be the main reasons for this problem. In addition, inhomogeneous particle movement in the process chamber and instability of the fluidizing pattern can also occur. To avoid these problems, Yoshinori et al. [30] developed a process chamber Fig. (15) with a converging conical end and a nozzle that is installed at the converging part of the container wall and sprays laterally directly into the fluidized bed. The atomizing and the fluidizing air can also be conditioned.
Fig. (15). Top spray apparatus with a converging conical ending [30].
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 particles through the gap between the air distribution base plate and inner column. Depending on the equipment and the batch size, more than one spraying nozzle can be used for providing enough amount of coating material on the core bed per time. Later, this construction has been further improved by regulating the temperature of the swirling air flow passing through the annular aperture [33]. The same inventor [34] has improved a bottom spray fluid bed equipment for coating of tablets. In this equipment, the wurster was removed to prevent the damaging of the tablets. Instead of perforations, the air distribution base plate consists of ducts arranged around the spray nozzle. Moreover, the peripheral part of the air distribution base plate is inclined towards the spray nozzle. This construction results in a controlled fluidization air flow, which guides the tablets into the spray zone. To improve the particle flow through the gap between the air distribution base plate and the wurster, Jones et al. [35] used additional air flows independent of the fluidization air flow 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 directly towards the inner column Fig. (17).
Fig. (18). a) Perforated housing b) Fluidized bed apparatus equipped with perforated housings [36].
Fig. (17). Wurster system with additional air flows of Jones [35].
Another example for changing the air distribution base plate design, is the top spray fluidized bed equipment by Jan [36], introducing a pair of perforated removable housings positioned vis--vis at the bottom of the processing chamber. One part of the fluidization air flow passes through these housings and flows in a circumferential manner into the processing chamber. Together with the other part of the fluidization airflow passing upwards through the base plate, this additional air movement produces a swirling motion enhancing 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 bottom spray system within a spherical product chamber. Return devices, which are commonly used in rotating pans, were installed at the top of the product chamber to support the
homogeneous circulation of core bed. The air distribution base plate consisted of concentric slits as previously described [17]. The width of the slits was adjustable, which allowed control over the amount and velocity of the air flow. This construction aimed to ensure a homogeneous and controlled circulating particle movement. The problem of this construction, however, is the risk of friction between the core bed and the return devices or the slits at the base plate. In contrast to the spherical Kugel Coater, the latest invention of Httlin [37] comprises a cylindrical processing chamber without return devices Fig. (19). The air distribution base plate consists of a concentric arrangement of overlapping guiding plates. This arrangement of the guiding plates provides a radial airflow moving the bed radially towards the wall of the process chamber, then upwards along the wall and then back to the centre of chamber. This homogenous circulation of the bed is maintained without friction between the core bed and the wall of the processing chamber. A multimedia nozzle is placed in the centre of the overlapping guiding plates, providing a horizontal spraying pattern directed parallel to the bottom of the chamber. This combination is designed to enhance both the fluidization of the bed and the distribution of the spraying liquid. For a detailed description of the multimedia nozzle please refer to section 2.4. 2.2.2. Spouted Bed Coaters Spouted beds have been developed as an effective alternative to fluidized beds for handling coarse particles over 2 mm diameter [38]. Following the direction of the spouting air/gas flow, the main parts of spouted bed equipment can be defined as air/gas inlet chamber, opening device, process chamber, spraying system and exhaust chamber. The air/gas inlet chamber comprises the lower part of the apparatus and - like in the fluidized bed system - can be implemented in single or divided form. Unlike the fluidized bed processes, the spouting air/gas does not enter the processing chamber through the air distribution base plate, but through an opening device with relatively high velocities, typically between 1 and 30 m/s Fig. (20). The opening device can be constructed as a central orifice or a
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.
longitudinal slot at the bottom. The process chamber is usually cylindrical with a conical base, in the centre of which the opening device is installed [39]. In general, the spraying system and the exhaust chamber are similar to those of fluidized bed systems. The construction of the opening device and the shape of the process chamber play an essential role in the particle movement and the particle velocity. In the following, the different designs for the opening device are described. Mrl et al. [40] have developed an opening device consisting two gorge-formed plates mounted on a connecting element Fig. (21). This construction provides two process chambers. In order to prevent both thermal damage of the feed material and heat loss by wall cooling, the chamber walls are constructed as double walls, which are arranged at a defined angle () and can be conditioned regarding their temperature. The connecting element is adjustable in its height and can therefore be used to change the openingwidth (h) of the gorge-formed device and adjust the airflow. Furthermore, it is possible to adapt the slots to affect the airflow. The problem of this design is the accumulation of debris on the slots, which interferes with the airflow pattern. Later, Mrl et al. [41] have modified the abovementioned opening device by providing a cylinder in the
Fig. (21). Spouted bed equipment with gorge-formed plates of Moerl [40].
lower region of the process chamber between the two walls Fig. (22). The cylinder rotates on its longitudinal axis and is equipped with an opening for the passage of the airflow into the process chamber. By rotating the cylinder it is possible to change the effective cross-section of the opening and to adjust the airflow. Jacob et al. enhanced the spouted beds by passing the spouting air through a gap instead of a cylinder Fig. (23)
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Fig. (22). Spouted bed equipment with rotating cylinder [41].
Fig. (23). The spouted bed of Jacob [42].
[42]. The airflow spouts the bed in an axial direction into the process chamber. The significant increase in the crosssection of the process chamber towards the top results in a sharp decrease of the fluidizing velocity and controlled airflow pattern. The distribution of coating liquid into the spouted bed is also improved by a special positioning of the spray nozzle. Thereby, the coating liquid is sprayed selectively and adjustably into the particle flow. Both top and bottom spray directions can be used. Further, in order to optimize the material movement and residence time of particles in each fluidizing chamber, Jacob et al. have further developed 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 spray spouted bed, Debayeux et al. [43] have modified the air/gas inlet chamber Fig. (24). Here, the air/gas inlet chamber consists of an upwardly converging conical part, which is linked to the process chamber by a cylindrical part of a
diameter (d) and a height of 0.5-0.66 d. The outlet of the spray nozzle is positioned in the cylindrical part of the air/gas inlet chamber directly below the connection to the process chamber. This positioning allows the airflow to form a particle-free pocket or pouch-like area above the nozzle. Thus, the spray pattern can fully develop before it comes in contact with the feed material. 2.2.3. Filter Systems The exhausting chamber, which is located at the upper part of the fluidized or spouted bed apparatus, is equipped with a filter system. Filter systems commonly consist of filter elements being responsible for removing dust or particles from the outlet air. The filter elements are usually made of textile bags, stainless steel multilayer screen fabrics, antistatic plastic sintered materials, or any other kind of pleated or un-pleated filter material.
Fig. (24). Modification of air/gas inlet chamber for improvement of spray pattern [43].
There are two conventional methods for cleaning the filter elements during the processing: (1) shaking systems and (2) reverse gas jets (back purge). In both cases, the removed dust falls back into the process chamber [21]. When utilizing filters with a shaking system, mechanical forces are used to clean the filter sacks. During the cleaning of the filter, the process airflow is stopped by closing an exhaust valve. After a certain cleaning time the shaking stops, and the process airflow is restarted by opening the exhaust valve. With this construction, the processing air/gas flow has to be stopped regularly. This can affect the coating process and consequently the properties of the end product. In order to solve this problem, double-chamber shaking filters were developed. Here, the exhaust chamber is divided into two separate shaking filters. During the cleaning of one filter segment, the other part of the filter remains active and maintains a continuous process airflow [21]. Double-chamber constructions have been designed also for back purge systems [44] Fig. (25). In this case, each filter cartridge is linked to a back-purge cleaning gas inlet which in turn is connected to a valve. This construction enables the consecutive cleaning of each cartridge while the other cartridges keep operating. Feldmann has improved the back-purge system by the installation 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/air from entering into the openings of the back-purge cleaning gas inlet. This construction contributes to the continuous jetting of back-purge cleaning gas. In order to avoid the presence of filter elements in the process chamber (which might affect the particle movement) and also to improve the cleaning of the filter system, a collar-shaped filter has been invented by Httlin [46]. Of note, 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 exhaust chamber. The filter surface consists of numerous removable small packets in a radial arrangement. These packets are made of multi-layer metal, anti static plastic material or textile and are seperated by narrow gaps. This construction provides a large surface for passage of the process air/gas through the filter. In case of clogging or damage of the packets, they can be easily removed rather than changing the whole system. In order to return the particles back to the process chamber, a back purge system is provided, which consists of a rotating cleaning air inlet rotating above the upper surface of the filter and blowing air consecutively into each packet Fig. (26). 2.3. Continuous Processing During the last two decades, continuous processing has been developed in order to overcome the disadvantages of
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Fig. (26). Collar-shaped filter of Httlin [46].
the batch concept, namely the low production rate and the scale up problem. To change a batch apparatus into a continuous one, feeding and discharging devices must be added. A feeding device consists of a reservoir for storing the feed material. From this reservoir, the feed material is guided into the continuous processing apparatus by a feeder providing variable feed rates. For this purpose, screw feeders or controllable rotary valves can be used. Indeed, the interplay between feeding rate and discharging rate defines the flow rate of the continuous process and determines the mean residence time of the particles [21, 31]. Different types of feeding and discharging devices have been described in detail elsewhere [21]. In the development of continuous processing, the first concept was based on a mono-cell apparatus equipped with feeding and discharging devices. This offered the possibility to operate exactly as with a batch apparatus [31]. This concept has been widely used in all coating technologies, including pan and fluidized bed coating. An example for such continuous pans rotating on horizontal axes is the invention of Ferrero, with a discharging device for removing the feed material at predetermined intervals during the process [47]. A recent invention in this field is the perforated drum of OHara et al. [48]. Here, a drum rotating on the horizontal axis is equipped with an adjustable feeding device providing the drum with a controlled amount or volume of feed material per unit of time. The discharging device consists of a weir plate of a defined structure, which allows the removal of a determined amount of coated feed material. The predetermined amount of feed material together with regular discharging enables the continuous processing. Moreover, this apparatus is equipped with an advanced cleaning system.
In case of the mono-cell continuous fluidized bed apparatus, particles reaching a pre-defined size are automatically discharged via the discharging pipe located at the centre of the process chamber. The air velocity within the discharging pipe can be controlled to achieve the desired classification of the 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 performing different processes in one apparatus, multi-cell continuous
devices have been developed. Rmpler et al. [22] have described a horizontal continuous fluidized bed apparatus in which the air/gas inlet chamber is divided. Due to this construction different fluidizing airflows with different temperatures can enter the equipment. Since the air flow and the air temperature can be conditioned, different processing steps can be carried out in separate parts of the processing chamber. 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 process units connected to each other. Each process unit consists of an air/gas inlet chamber, an air distribution base plate, a process chamber, a filter system and a spraying system. During the coating process, the feed material is conveyed pneumatically. Controlled recirculation of particles occurs within each unit and a controlled spray is applied to the feed material in order to produce homogeneous distribution of coating material on the bed. One example of continuous spouted bed has already been mentioned in the section 2.2.2. [23], Fig. (29). This apparatus
consists of at least two processing units, connected to each other with an overflow channel. Each processing unit is equipped with an airflow device, an inlet wall and return flow wall, an outlet filter and a spraying system. The inlet and the return flow walls form a cone. The inlets of the opening device can be shaped into a gap, perforated sheets or throttled baffles, which set the amount of supplied fluidizing air. Due to a second air flow across the spouted air flow, the feed material passes through the overflow channels between the processing units. The overflow channels can also be formed as cross-sectional openings, arbitrary transport systems, etc. The processing conditions in the individual processing unit can be set according to the conditions required for the material treatment. 2.4. Spraying Systems Most coating processes involve the addition of one or more liquids to the system. In order to achieve good process conditions, liquids have to be processes into very small droplets using nozzles. The spraying nozzles used in coating technology 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 spray nozzles are available: (1) the hydraulic or so-called onemedia nozzle and (2) the pneumatic nozzle Fig. (30). Hydraulic or one-media nozzles are airless nozzles supplied with high-pressure pumps that expose the coating liquid to atomizing pressures (50-150 bar). Using pneumatic nozzles, the coating liquid is accelerated to high speed by means of compressed air. For this purpose, atomizing pressures of 0.5-6 bar are usually applied. The conventional form of a pneumatic nozzle is the so-called 2-media nozzle, referring to liquid as the first medium and atomizing gas or air as the second. Generally, in two-media nozzles the opening for the coating liquid is surrounded with an air gap, where the atomization gas/air is guided to the liquid opening tip. At the opening tip, the relatively slow flowing liquid comes in contact with the rapid gas stream. The resulting shearing forces atomize the liquid stream and produce a very fine mist. One advantage of pneumatic nozzles is the larger opening for the coating liquid, in comparison to the opening of hydraulic nozzles. In the case of spraying suspensions, dispersions and fluids with high viscosity, this larger opening offers a reduced tendency of clogging of the nozzle. In addition, both spray rate and fluid delivery rate are easier to control using pneumatic nozzles [1, 24]. Therefore, pneumatic nozzles are typically used 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 designs can be distinguished Fig. (30). Conventionally, the liquid to gas contact takes place just in front of the opening tip. This kind of pneumatic nozzle design is called external mixing. In the case of internal mixing, the tip of the liquid opening is inside the gas cap. Liquid and gas are mixed prior to leaving the nozzle. The spray pattern affects the particle wetting and the local liquid distribution in the core bed, which consequently
influences coating properties such as porosity, surface roughness and density. Generally, there are 3 different spray patterns: full cone, hollow cone and flat jet pattern [21] Fig. (30). In fact, each pattern is suitable for a main spraying purpose. The hollow cone pattern is usually used for granulation and wetting purposes, whereas the full cone and flat jet patterns are typically used in coating processes. The flat jet spraying pattern aims to improve the micronization of liquid droplets with a relatively low air flow and low air pressure [50]. As pneumatic nozzles with full cone or flat jet spraying patterns are in demand in the pharmaceutical industry, this section will focus on this type of nozzles. In the following, improvements in different types of nozzles will be discussed. In general, most inventions aimed to enhance the spray pattern, to prevent the clogging of the nozzles and to facilitate in-process cleaning. External Mixing Nozzles with Flat Jet Spraying Pattern The conventional method for obtaining a flat jet spraying pattern is using flat jet caps with two deflecting flanges or so-called horns. These horns are placed vertically to the longitudinal nozzle axis. The horns are provided with openings for airflows, which are responsible for forming a defined jet pattern Fig. (31). The central channel for the coating liquid is surrounded by a channel for atomizing air. The coating liquid is atomized in front of the opening tip due to this atomizing air. At the same time, a defined jet pattern forms due to the airflows guided towards their openings in each horn and towards the atomized coating liquid. In the conventional model, the angular shape of the horns and the relatively long distance between the atomizing air openings and the central liquid opening cause the deposition of coating material on the surface of the flat jet cap. This potentially impairs the coating quality. Thus, Gerstner [51] has invented an external mixing nozzle with a flat jet cap providing 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.
Fig. (31). Spray nozzle with conventional flat jet cap.
Furthermore, transitional regions between the deflecting surface and the lateral surfaces are rounded off in order to avoid edges. The atomizing air openings producing the flat jet 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 and the short distance between the flat jet air flow openings and the central positioned liquid opening prevent the depositing of coating material on the deflecting surface (the so-called beard building). Referring to this characteristic, the described caps are marketed as ABC-Technique (Anti Bearding Caps).
mixing nozzle. While the construction of a flat jet cap with horns is maintained, this invention introduced internal mixing of coating liquid with the atomizing air before leaving the nozzle. The atomized fluid becomes a jet pattern after leaving the nozzle due to the airflows guided through the openings in the horns and towards the atomized coating fluid [52]. An example for the improvement of internal mixing nozzles with conical spraying pattern is the invention by Gianfranco [53]. In this invention, the channels for spraying liquid and atomizing air were formed into conical shape in order to produce more homogeneously atomized droplets with low speed. The channel for atomizing air consists of two 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 first converged-shaped part of the atomizing air channel. The atomizing air accelerates at a substantially higher volume as compared to the spraying liquid and impinges the liquid. This results in acceleration and atomization of the spraying liquid. Due to the diverged-shaped part before the opening tip, the atomized liquid leaves the opening with reduced speed Fig. (33). Multi-Media Nozzles In order to provide fine and homogeneous droplets, a three-media spraying system has been developed by Httlin [54]. This spraying system consists of three concentrical flow channels running from the inflow along a longitudinal axis to the opening tip Fig. (34). The spraying liquid channel is both internally and externally surrounded by additional channels for spraying and guiding atomising air. While the spraying air is responsible for atomizing the coating liquid, the guiding air is intended to facilitate the targeted spraying of this liquid on the surface of feed material. In order to avoid the drying of the spraying liquid inside the nozzle as well as clogging of the nozzle, the guiding air (the so-called Mikroklima) can be conditioned with different temperatures for example. In the modified form of this invention, the channels are directed outwards from the longitudinal axis towards their opening at an angle of 15-90 [55]. This
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 to improve the micronization of the coating liquid when using low air flow, Harruch has invented a modified internal
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Fig. (33). The internal mixing nozzle of Gianfranco [53].
Fig. (34). Multi-media nozzle [54].
structure results in the diverged distribution of atomised coating liquid, and is intended to achieve two aims: (1) to avoid the overlapping of produced droplets and consequently to prevent the formation of large drops, and (2) to obtain a wide angled spray cone. Depending on the properties of the liquid to be sprayed, the size of the spraying liquid channel can be regulated. Moreover, the walls enclosing this channel are rotatable in opposite directions around the nozzle axis which aims to prevent the clogging of the nozzle. Prevention of the Clogging of Nozzles As mentioned before, the larger liquid opening of pneumatic nozzles decreases the tendency of clogging as compared to hydraulic nozzles. Nevertheless, the clogging of two-media nozzles remains a serious problem in the case of pneumatic nozzles, particularly during the process. In the general design of the two-media nozzles, the coating liquid insert is connected to the nozzle body with a curve of 90. This connection area is the favourite place for deposition of coating material and preferentially causes clogging of the nozzle. In order to overcome this problem, Beckendorff [56] has designed an external two-media nozzle, avoiding the curve of 90 by the connection of coating liquid insert and liquid channel in the nozzle body. In the modified nozzle by Beckendorff, the nozzle body holds a removable liquid insert, which is connected to an axial liquid channel and is surrounded by the atomizing air channel. Luy et al. [57] have designed a removable two-media spraying nozzle and an enclosing body, particularly for using in fluidized bed equipments with a bottom spray system. The enclosing body consists 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 the bottom of the fluidized bed device utilizing air pressure. In case of clogging of the nozzle during the process, this structure enables the in-process removal and cleaning of the nozzle. An axially adjustable cleaning needle present in the middle of the nozzle is connected with an actuation equipment for cleaning the nozzle during the process. Grieb et al. [58] have developed a 2-media spray nozzle with a flexible cleaning cap, made of silicon or another elastic material, which is arranged around the nozzle cap. A feed for atomizing the cleaning air is arranged between the nozzle body and the cleaning cap. The atomized cleaning air provides continuous bulge and vibration of the cleaning cap resulting in the removal of product deposition at the nozzle outlet. Depending on the aim of coating or the composition of the spraying liquid formulation, it is sometimes necessary to spray different media separately at the same time. For this purpose, a nozzle was invented [59] with separate channels and openings for passage of different liquids. The openings for different liquids and the opening for atomizing air form concentric circles. Schlick GmbH [60] has developed a nozzle containing a detachable fluid channel in the case of spraying different liquids one after the other. In another invention [61] from the same company, individual spray nozzles are interconnected to each other by adapters with respective channel outlets. This invention is intended to prevent the problem of cleaning the nozzle during the process by using more than one spraying liquid and to enable the use of different types of nozzles during one process.
3. CURRENT & FUTURE DEVELOPMENTS Independent of the type of coating technology used, advanced coating properties can only be achieved if the manufacturing process is fully understood and controlled. This understanding and controlling of the manufacturing processes is the aim of PAT ( Process Analytical Technology) a new FDA initiative. PAT is defined as a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and inprocess materials and processes with the goal of ensuring final product quality [62]. Therefore, the objective of the PAT framework is to design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing process. The methods employed to achieve this goal can be categorized as: Multivariate data acquisition and analysis tools Modern process chemistry tools analyzers or process analytical
radioactively labelled tracer particle has been tracked within a bed of similar but unlabelled particles [65]. The circulation time, circulation time distribution and the number of passes of the cores during the coating process in a wurster system have been investigated using magnetic tracer technology. The impact of changes in design and process parameters on the movement of particles and the occurrence of dead zones has been studied using this technique [66, 67]. Particle density and velocity have been measured in a horizontal rotating pan and subsequently in a vibrating fluidized bed using magnet resonance imaging (MRI) [68, 69]. Walker et al. used Raman spectroscopy in order to provide 3D maps of the density and chemical structure of particles in a fluidized bed equipment. The information gained was further used for the analysis of air flow dynamics [70]. Dressler et al. have employed microwave sensor devices for measurement, monitoring and controlling of the particle movement in fluidized or spouted bed equipments during the spraying process for coating and granulation. For this purpose, microwave radiation was directed into the core bed and the radiation reflected by particles was measured [71]. Monte Carlo Modelling The Monte Carlo method is a quantitative modelling procedure for predicting outputs expected from theory and experiment. It is performed by random sampling from probability distributions of parameters influence the process, such as core bed temperature, rotation speed of drum, physical properties of coating material, etc. Following the assumption that a process consists of several events, the parameters affect these events in such a way that a probability distribution is obtained. The average of all outputs of these randomly sampled probability distributions will yield accurate estimates of the outputs of real processes [2]. Several investigators have used Monte Carlo modelling for studying the effect of coating parameters including coating period, air velocity, mixing rate of the particles and spray pattern on the coating mass distribution. Particle movement and spray dynamics in both the fluidized and pan coaters have also been simulated utilizing this method of modelling [72-74]. The determination of coating uniformity and weight uniformity of coated tablets during the pan coating process using the Monte Carlo method was patented by Choi [75]. Improvements in the programming of this modelling were undertaken in order to make the method more suitable for simulating high speed particle movements and to accelerate parallel processing [76, 77]. According to current expert opinion, however, a priori prediction is not possible using phenomenological and Monte Carlo modellings, and certain model parameters should first be measured experimentally [2, 63]. Discrete Element Modelling (DEM) and Computational Fluid Dynamics Modelling (CFD) Using DEM and CFD simulations, pre-adjustment of model parameters is not necessary. The DEM and CFD are
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 available tools separately and in detail. Instead, modern analytical and monitoring tools for coating processes, which are supported by PAT will be discussed. 3.1. Analytical Methods for Process Understanding and Controlling In this section, different methods for analysis, design and control of the coating processes are reviewed without going into to much detail about underlying mathematical operations. For the interested reader, however, the relevant literature will be presented in each section. The commonly used methods for process analysis are divided into probabilistic and numerical methods. The phenomenological and Monte Carlo modellings are part of the probabilistic methods, whereas the computational fluid dynamics (CFD) simulations and the discrete element modelling (DEM) are numerical calculations. Turton [63] and Pandey et al. [2] reviewed these methods with emphasis on their application for modelling coating mass uniformity. In the following, their applicability for process analysis and controlling will be summarized. The utilization of linear and non-linear methods for process characterization and optimization will also be described. Phenomenological Modelling With this type of modelling, the process under study is considered to consist of several events, whereas the final process represents the sum of these events [2]. Different techniques have been used to investigate particle flow pattern, particle density and velocity, and circulation time in the pan and fluidized bed coaters. Positron emission particle tracking (PEPT) has been used to investigate the particles flow pattern in a rotating drum [64] and in an interconnected fluidized bed reactor. Using PEPT, the motion of a single
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numerical simulation tools. These types of modellings are widely used for the investigation of flow patterns and gassolid interactions in fluidized and spouted beds [78-84]. Generally, there are two types of calculation options, the trajectory and the continuum media method. CDF modelling simulates the solids and gas flow in a continuum manner using Navier-Stokes equations. In contrast, DEM is one of the trajectory models, in which particle-particle and particlegas interactions are simulated by tracking them individually. To describe the dynamics of both the gas and particle phase, continuum (Eulerian) and discrete (Lagrangian) types of models are employed. DEMs describe the gas phase as a continuum, whereas each of the individual particles is treated as a discrete entity and traced individually utilizing the Newtonian equation of motion [85, 86]. Deen et al. [85] reviewed the different approaches of DEM, i.e. the hardsphere and the soft-sphere systems, their applications in the investigation of flow patterns in fluidized beds, and the different particle-particle and gas-particle interactions. DEM simulations have been used by Limtrakul et al. [87] for the investigation of the mixing behaviour in a vibrated fluidized bed equipment. The effect of particle type, amplitude and frequency of vibration and air velocity on the flow pattern of particles has been studied. Wang and Rhodes [88] have used these types of modellings for the investigation of the particle mean residence time near the walls of a fluidized bed, as well as for the study of distance between particles and container wall and particle to particle contact frequency. In order to make the CFD simulations suitable for process controlling, Colman and Townsen have improved this type of modelling for real-time simulations [89]. Aiming to decrease the overall processing time, Duggleby and Ball transferred the computationally complex CFD calculations to a dedicated coprocessor [90]. Dewhurst has provided a CFD modelling software publically available via world wide web. By logging on to the server computer and using the client software, one can select the individual application among different categories of engineering applications which are offered in a menu. By giving the requested data, the server computer models the specified problem, prepares the results in an output form and informs the customer per email [91]. Linear and Non-Linear Calculation Methods The influence of process parameters and coating formulation on the end product quality can be investigated by using the design of experiments (DOE) with appropriate statistical analysis and regression. This method is useful for indicating the relative significance of a number of independent variables and their interactions responsible for the obtained result. A disadvantage of this method is the dependency of DOEs on predetermined statistical significance levels, as less significant terms are not included in the models [92-94]. Non-linear calculation methods such as Artificial Neural Networks (ANNs) offer an alternative to DOEs. ANNs are models of a totally different kind, in which all available data are used for making the models more accurate. Therefore, they are able to predict response values for optimization and validation purposes more precisely than DOEs. ANNs consist of a set of mathematical methods and algorithms designed to mimic the basic functions of the human 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 the inputs that the processing unit receives, apply a transfer function to the summed inputs and produce an output, respectively. A number of different network-learning processes is available, amongst which the feed-forward back propagation is the most widely used. Typically, this type of network uses processing units placed in three types of layers, input, hidden and output, which is also termed a multi-layer perceptron (MLP). Each unit within one layer is connected to units in adjacent layers with an associated weight. It is the adjustment of these weights which is undertaken during network training, as network training involves iteratively changing the weights between neurons until the output signal matches the target output within a desired error minimum. Finally, a regression coefficient may be calculated based on the observed product properties and network predicted values [96]. The DOEs and ANNs are particularly useful for process and formulation optimization but ignore the physics behind the process. Different investigators have used them for characterization and optimization purposes. Barletta et al. [97] have investigated the influence of coating time, applied voltage and air flow rate on the coating properties in an electrostatic fluidized bed utilizing both DOEs and ANNs and compared the accuracy of these two methods. Salar Behzadi et al. [98] have used ANNs for the validation of a modified fluid bed equipment for granulation processes. Vaithiyalingam et al. and Salar Behzadi et al. have used DOEs and ANNs for formulation development purposes [99, 100]. In order to avoid complex calculations for the determination of the thickness distribution of coating layers, Eickmeyer et al. combined a phenomenological model with artificial neural networks [101]. Using this combination, the specified known parameters are directly supplied to the phenomenological model as fixed input parameters. Those parameters whose effects on the spraying results are unknown should be supplied to an ANN. After treatment by means of the network and investigation of the effect of these parameters on the spraying results, they will add to the specified parameters in the phenomenological model. A method for optimization of the artificial neural networks has been patented by Schaffer et al. [102]. The patent represents the architecture of the neural networks by symbol strings. An initial population of networks is trained and evaluated. The strings representing the fittest networks are modified according to a genetic algorithm and the process is repeated until an optimized network is produced. 3.2. End Point Monitoring The quality of a pharmaceutical end product should be ensured during the manufacturing process. Monitoring the process end point is an important tool for manufacturing a product with predefined quality. During the last decades, application of process measurement tools based on spectroscopic techniques, particularly near infrared (NIR) reflectance and Raman spectroscopy, have gained importance for the monitoring of different steps of pharmaceutical processes. In general, their popularity is based on the versatility, the minimal sample preparation and the non-destructive nature of these methods. Moreover, remote fiber optic probes
have enabled the use of NIR and Raman spectroscopy for the in-line investigation of pharmaceutical manufacturing processes and the determination of the process end point. However, the influence of physical properties on spectra and the need for calibration using a reference technique obviously represent the major drawbacks of this technique. NIR spectroscopy has been the leading analytical method for pharmaceutical processes for many years. Several investigators have used the NIR reflectance spectroscopy for at-line analysis of tablet film coating. For instance, changes in coating thickness were determined by evaluating changes in the NIR reflectance spectra of the tablet surface [103105]. Positioning a defuse reflectance fiber-optic probe inside the coating equipments enabled different investigators to analyse the in-line of film coating processes using NIR spectroscopy. Andersson et al. have analyzed the coating thickness of pellets by NIR spectrometry and by using a multivariate calibration method in a fluid bed equipment [106]. Perez-Ramoz et al. have monitored the pan coating process of tablets. The thickness of the coating was determined by monitoring the decrease of NIR absorption bands characteristic of a component of the tablet core and monitoring the increase of NIR bands characteristic of a component in the coating material. Quantitative calibration of NIR spectra was developed for the tracking of the coating thickness [107]. Several steps of a manufacturing process such as melt granulation, tableting of granules and coating the tablets have been analyzed at-line using Fourier transform (FT)-NIR and infrared imaging spectroscopy coupled to a microscope and equipped with a focal plane array (FPA) detector. The effect of time and temperature on the quality of melt granules, the effect of compact force on the quality of tablets and the effect of coating time and formulation on the quality of coated tablets have been investigated [108]. The use of Raman as process analytical method is quite limited compared to the use of NIR. This is due to the expensive Raman equipments on the one hand and the sensitivity of Raman to interfering background light scattering on the other hand. Nevertheless, given its versatility and the continuous progress in its efficiency, Raman spectroscopy is believed to develop into a powerful analytical method complementing NIR. Examples of applications using Raman are polymorph screening and (in-line) monitoring of blending and coating processes [109-112]. Romero-Torres et al. have used Raman spectroscopy with multivariate calibration for the investigation of coating thickness of tablets coated in a pan coater [113]. In another study, the same authors have evaluated different calibration methods for using Raman spectroscopy as an analytical tool for the investigation of coatings comprising fluorescent ingredients [114]. El Hagrasy et al. have used non-contact Raman fiber optic probes for in-line monitoring of coating in a pan coater. The effect of the pan rotation speed on the acquired signal was investigated. Moreover, a quantitative calibration method was developed for the determination of coating kinetics and end point [112].
As mentioned above, application of remote fiber optic probes facilitates in-line process monitoring with IR or Raman spectroscopy. The first remote fiber optic probe for Raman spectroscopy was reported by Schwab and McCreery [115]. In simple terms, it consisted of 2 single optical fibers, one for delivering the laser light to the sample (the so-called excitation fiber), and one for collecting the light scattered by the sample and transmitting it to the detector (the so-called collection fiber). The efficiency of exciting and collecting Raman photons from any individual point in the sample, however, was poor. Therefore, several developments have been undertaken to improve the efficiency and increase the intensity of Raman signal. Examples are using multiple fibers instead of one collection fiber and changing the overlap between the emission cone of the excitation fiber and the collection cones of the collection fiber in order to increase the collection efficiency [116]. Another improvement involved the coating of the interior surface of the sample chamber in order to prevent the reaching of interfering light to the collection fiber. This coating comprised adhesive and light-absorbing particles such as carbon black. Moreover, Raman spectrum was measured using two different pressures. The first measurement was used as blanc. The design of the probe prevented the exciting light from entering the collection fiber and interfering with the Raman signal [117]. Improvements in the design of excitation and collection fibers have further been undertaken in order to increase light coupling efficiency and consequently enhancement of signal intensity [118]. Using additional optical elements enabled the collection of spectra from larger areas of the sample under study (spot sizes of 1 mm or greater) compared to conventional optical elements which utilize spot sizes of 2-60 m. The larger spot size facilitates the collection of statistically useful data from inhomogeneous samples, which is a benefit for in-line process monitoring [119]. Improvements in probe housing have also been undertaken to facilitate the cleaning of the optical window during the processing and facilitate the in-line monitoring [120, 121]. 4. CONCLUSION In recent decades, coating of pharmaceutical dosage forms has been subject of remarkable developmental efforts aiming to ensure and enhance end product quality. Improvements regarding particle movement, heat and energy transfer, film distribution, drying efficiency and continuous processing have contributed to significantly develop this technology. However, evaluation and success of further constructional improvements in coating methods appear to depend on accurate analytical tools and advanced methods for process modelling and control. In this regard, achieving optimal manufacturing efficiency and high end product quality still remains a key challenge for future research efforts. Given the recent claims of the FDA to pursue regulation of end product quality during the manufacturing process (Quality by Design), future developments should strengthen the improvement of more powerful analytical, monitoring and management tools in order to ensure the control of all decisive parameters.
Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63]
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Recent Patents on Drug Delivery & Formulation 2008, 2, 209-230

Innovations in Coating Technology

Salar Behzadi et al.

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

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

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

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

Salar Behzadi et al.

Fig. (6). Accela Coata [9].

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Salar Behzadi et al.

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Salar Behzadi et al.

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Salar Behzadi et al.

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

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

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

Salar Behzadi et al.

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

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

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

Salar Behzadi et al.

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

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

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Salar Behzadi et al.

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

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

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

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

Salar Behzadi et al.

Innovations in Coating Technology

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Salar Behzadi et al.

Innovations in Coating Technology

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